Ted derivatives thereof process for the preparation of desaandrostanes pregnanes and unsatura

ABSTRACT

THIS INVENTION IS DIRECTED TO PROCESSESS FOR THE PREPARATION OF DESA-ANDROSTANES, PREGNANES AND UNSATURATED DERIVATIVES THEREOF BY PYROLYZING THE ALKALI METAL SALT OF THE CORRESPONDING 3,5-SECO-3-OIC ACID. THE INTERMEDIATES PREPARED IN ACCORDANCE WITH THE PROCESS OF THIS INVENTION ENABLE THE PREPARATION OF 9B,10A-STEROIDS WHICH ARE PHARMACOLOGICALLY USEFUL AS ANABOLIC, ANTI-ANDROGENIC, PROGESTATIONAL AND SALT-RETAINING AGENTS.

United States Patent 3,758,508 PROCESS FOR THE PREPARATION OF DESA- ANDROSTANES, PREGNANES, AND UN- SATURATED DERIVATIVES THEREOF Milan Radoje Uskokovic, Upper Montclair, N.J., assignor to HofImann-La Roche Inc., Nutley, NJ.

No Drawing. Application June 17, 1968, Ser. No. 737,361,

now Patent No. 3,704,324, which is a division of application Ser. No. 499,094, Oct. 20, 1965, now Patent No. 3,574,761, which in turn is a continuation-in-part of application Ser. No. 400,206, Sept. 29, 1964, now Patent No. 3,412,107. Divided and this application May 24, 1971, Ser. No. 146,483

Int. Cl. C07d 11/00 US. Cl. 260-338 28 Claims ABSTRACT OF THE DISCLOSURE This invention is directed to processes for the preparation of desA-androstanes, pregnanes and unsaturated derivatives thereof by pyrolyzing the alkali metal salt of the corresponding 3,5-seco-3-oic acid. The intermediates prepared in accordance with the process of this invention enable the preparation of 9,8,l0a-steroids which are pharmacologically useful as anabolic, anti-androgenic, progestational and salt-retaining agents.

RELATED APPLICATIONS This application is a division of applicants copending application Ser. No. 737,361, filed June 17, 1968, now Pat. No. 3,704,324 which is a division of applicants copending application Ser. No. 499,094, filed Oct. 20, 1965, now Pat. No. 3,574,761 entitled Intermediates and Processes, which is a continuation-in-part of applicants copending application Ser. No. 400,206, filed Sept. 29, 1964, now Pat. No. 3,412,107 entitled Intermediates and Processes.

DETAILED DESCRIPTION OF THE INVENTION This invention relates to novel chemical intermediates and processes useful in the preparation of steroids. Natural steroids possess a 9a,l0B-stereochemical configuration. Steroidal compounds possessing the unnatural 9 3,100:- configuration represent a pharmaceutically valuable class of compounds which, even though numerous members are known in the art, cannot be obtained by totally classical chemcial means. In fact, the only known methods for obtaining steroids possessing the unnatural 9B,10u-configuration involve at least one photochemical reaction. Such photochemical reactions involve irradiation with ultraviolet light of strong intensity for long periods of time and, in comparison with purely chemical reactions, are very inefiicient and give only small yields.

It is an object of the present invention to provide intermediates and processes which enable the preparation of 95,10a-steroids without the necessity of proceeding through a photochemical reaction. It is also an object of this invention to provide novel intermediates and processes which will enable the further exploration of steroids having the 60 unnatural 9,8,l0wc0nfiguration. It is also an object of this invention to provide novel 93,10a-steroids.

The novel intermediates and processes of this invention are valuable and provide a new synthetic route completely of a classical chemical nature, i.e. involving no "ice photochemical reaction, for converting steroids having the normal configuration into steroidal compounds possessing the unnatural 9fl,l0a-configuration.

In one aspect, the novel intermediates and processes 5 of this invention enable the preparation of 9fl,l0a-steroids of the androstane series of the formula mo R1 I 10 Ba H30 H i wherein R is, individually, selected from the group consisting of hydroxy and lower alkanoyloxy; R is, individually, hydrogen or lower alkyl and R and R taken together, are selected from the group consisting of (l7/3-OH, l7a-lower alkanoic acid lactone) and oxo; R

is selected from the group consisting of hydrogen, lower alkyl, hydroxy and lower alkanoyloxy; Y is selected from the group consisting of hydrogen and lower alkyl and X is a substituent in the 6- or 7-position selected from the group consisting of hydrogen, lower alkyl,

lower alkylthio, lower alkanoylthio and halogen.

Compounds of Formula I are useful as anabolic agents.

Other 9B,l0u-androstanes, the preparation of which is enabled by the intermediates and processes of this invention, are of the formulae H3O R1 --lower alkenyl (III) wherein R R Y and X have the same meaning as above Compounds of Formula III are useful as progestational agents and compounds of Formula II are useful as antiandrogenic agents.

In another embodiment of this invention, the novel compounds and intermediates provided by this invention enable the preparation of 93,10a-sterids of the 17/3- pregnane series of the formula Compounds of Formula IV are useful as progestational agents.

Oth'er 9B,'10a-steroids of the 17B-pregnane series, preparable from the novel compounds and process of this invention, are of the formula wherein R' R' Y and X have the same meaning as above.

Compounds of Formula V are useful as salt-retaining agents, i.e. are useful in the treatment of Addisons disease.

As used herein, the term lower alkyl comprehends both straight and branched chain saturated hydrocarbon groups, such as methyl, ethyl, propyl, isopropyl and the like. Similarly, the term lower alkanoyl comprehends groups such as acetyl and the like, and the term lower alkanoyloxy comprehends groups e.g. formyloxy acetoxy and the like. In the same manner, the term lower alkenyl comprehends groups such as vinyl and the like, and the term lower alkynyl comprehends groups such as ethinyl and the like. Halogen comprehends all four halogens, i.e. iodine, bromine, chlorine and fluorine.

The expression (l7B-OH, l7a-lower alkanoic acid lactone) refers to a configuration on the C-17 carbon atom illustrated as follows:

wherein W is lower alkylene, e.g. polymethylenes such as ethylene, propylene or the like.

With respect to substituents in the 6- and 7-position, preferred compounds are those having hydrogen or lower alkyl in 6- or 7-position, and those having halogen in the 7-position.

In one aspect, this invention comprises a method for the preparation of 95,10a-androstanes of Formulae 1-111 and of 9 8,1Oa-17fi-prcgna cs of Formulae IV-V Which comprises the hydrogenation of desA-androst-9-en-5-ones or of desA-17fl-pregn-9-en-5-ones to 95,10fl-desA-androstan-S-ones or 9B,1013-desA-17fl-pregnan-5-ones, respectively, followed by condensation with a lower alkyl vinyl ketone with methyl or ethyl vinyl ketone preferred (as well as substitutes therefor such as l-tertiary amino- 3-butanone, 1-tertiary amino-3-pentanone and quaternary ammonium salts thereof), l-Q-butan-3-one, 1-Q-butan-3- one lower alkylene ketal, 1-Q-butan-3-ol, esterified l-Q- butan-3-ol, 1-Q-butan-3-ol ether, 1,3-dichlorobut-2-ene, 1,3-dichlor0pent-2-ene, l-pentan-3-one, 1-Q-pentan-3-one lower alkylene ketal, 1-Q-pentan-3-ol, esterified l-Q-pentan-3-ol or l-Q-pentan-3-ol ether, which condensation yields the desired 95,10ot-St610ld8. The symbol Q is bromine, chlorine or iodine, with the former two being preferred. This invention also provides a number of different methods for the preparation of said desA-androst-9- en-S-one or desA-17B-pregn-9-en-5-one starting materials from natural steroids.

In one embodiment, a steroid of the 3-oxo-androst-4- ene or 3-oxo-l7 3-pregn-4-ene series is subjected to an oxidative ring opening of the A-ring yielding a S-oxo-3,5- seco-A-norandrostan-3-oic acid or a 5-oxo-3,5-seco-A-norl7p-pregnan-3-oic acid, which 3-oic acid can then be converted to a mixture of a l0u-desA-androstan-5-one and a IOfl-desA-androstan-S-one or a mixture of a 10mdesA-17flpregnan-5one and a 10/3-desA-l7B-pregnan-5- one. The conversion of the 3-oic acid to the desA-compound can be effected either by pyrolysis of a salt of said 3-oic acid or via the enol lactone, i.e. a 4-oXoandrost-5- en-3-one or a 4-oxo-17fi-pregn-5-en-3-one, which upon reaction with a Grignard reagent gives an aldol, which in turn can be converted into the desired desA-compound. The desA-compound can then be converted into the starting material desA-androst-9-en-5-one or desA-l7fl-pregn- 9-en-5-one via a two-step sequence of halogenation and dehydrohalogenation.

In another embodiment of this invention, desA-androst- 9-en-5-one or desA-l7fl-pregn-9-en-5-one starting materials can be prepared from ll-hydroxy steroids of the 3- oxo-androst-4-ene or 3-oxo-l7B-pregn-4-ene series. This can be eifected in a variety of ways. In one approach, an ll-hydroxy group of a steroid of the 3-oxo-androst-4-ene or 3-oxo-17B-pregn-4-ene series is converted into a leaving group, for example, a sulfonic acid ester or carboxylic acid ester. Oxidative ring opening of the A-ring of the thus formed ll-(esterified hydroxy)-containing compound yields the corresponding ll-(esterified hydroxy)-5-oxo- 3,5-seoo-A-norandrostan-3-oic acid or ll-(esterified hydroXy)5-oxo-3,S-seco A nor 17,6 pregnan-3-oic acid which upon pyrolysis of a salt of said 3-oic acid yields the desired desA-androst-9-en-5-one or desA-l7fl-pregn-9- en-S-one starting material.

A further approach involves formation of an ll-hydroxy desA androstan-S-one or ll-hydroxy-desA-l7apregnan-S-one from an ll-hydroxy steroid of the 3-oxoandrost-4-ene or 3-0Xo-l7/3-pregn-4-ene series via an oxidative ring opening of the A-ring of said ll-hydroxy steroid which yields an l1-hydroxy-5-oxo-A-nor-3,S-secoandrostan-3-oic acid 3,1l-lactone or an ll-hydroxy-S-oxo- 3,5-seco-17,6-pregnan-3-oic acid 3,1l-lactone which, in turn is converted into a salt of the corresponding keto acid which salt upon pyrolysis gives the ll-hydroxy-desA- androstan-S-one or ll-hydroXy-desA--pregnan-5-one. Esterification of the ll-hydroxy moiety of the so-obtained compound with an acid moiety yields an ll-(esterified hydroxy)-desA-androstan-5-one or an ll-(esterified hydroxy)-desA-l7}3pregnan-5-one which upon elimination of the leaving group (i.e., the esterified hydroxy moiety) gives the desired desA-androst-9-en-5-one or desA-17ppregn-9-en-5-one starting material. Though, in the above reaction sequence either Ila-OH or llfi-OH starting material steroids can be used, it is preferred to use Ila-OH starting materials.

As will be appreciated from the above discussion, neither the specific reaction steps nor the reaction sequences of this invention involve any modification of substituents found in the 16- and/or l7-position of the starting material natural steroids. However, in order to obtain unnatural 9[3,10a-steroids of Formulae LV, it is necessary or desirable to protect certain of the 16- and/or 17-substituents against one or more of the reaction steps involved. It is also convenient to initially protect such a substituent in the starting material natural steroid and maintain the substituent in its protected form throughout the entire reaction sequence, regenerating the desired substituent only when the steroid of Formula I-V possessing the unnatural 9;8,l0a-configuration is obtained. On the other hand, it is sometimes convenient to insert a protecting group only before a certain reaction step or sequence of reaction steps. Said protecting group can then be maintained until the final reaction step or can be split off at some intermediate stage. The protecting groups can be inserted and split oil? by means know per se. The desirability of having protecting groups present will be further discussed below when the specific reaction steps are discussed in detail. The various substituents which are susceptible to being protected are exemplified by the 16- hydroxy group in a compound of any of Formulas IV, the 17fl-hydroxy group in a compound of any of Formulas I-III, the 17a-hydroxy or 20-oxo group in a compound of any of Formulas IV-V, the 21-hydroxy group of a compound of Formula V or the 17-oxo group of a compound of Formula I.

The 17-oxo or 20-oxo group is suitably protected by ketalization, i.e., by reaction with a lower alkanediol, to yield a 17-lower alkylene dioxy or 20-lower alkylene dioxy compound, i.e., a l7-ketal or a ZO-ketal.

The 16-hydroxy, 17a-hydroxy, 17b-hydroxy or 21-hydroxy moieties can be protected by esterification and/or etherification of the hydroxy group. Any available acid which will form an ester that can subsequently be hydrolyzed to regenerate the hydroxy group is suitable. Exemplary acids useful for this purpose are lower alkanoic acids, e.g. acetic acid, caproic acid, benzoic acid, phosphoric acid and lower alkane dicarboxylic acids, e.g. succinic acid. Also, protection for tthe 16u-hydroxy, 17a-hydroxy, or 21-hydroxy substituent can be efifected by forming the lower alkyl ortho ester thereof, i.e. 1604,1704- or 170:, 21-lower ortho esters. A suitable ether protecting group is, for example, the tetrahydropyranyl ether. Others are arylmethyl esters such as, for example, the benzyl, benzhydryl and trityl ethers, or a-lower alkoxy-lower alkyl ethers, for example, the methoxymethyl, or allylic ethers.

In compounds containing the dihydroxyacetone side chain at C-17 (for example, compounds of Formula V wherein R is hydroxy), the side chain at 0-17 can be protected by forming the 17,20; 20,2l-bis-methylenedioxy group or by forming a 17,21-acetal or ketal group, or by forming a 17,21-diester. The 17,21-acetal or ketal and 17,21-diester hinder the ZO-ketone group and minimize the possibility of its participating in unwanted side reactions. On the other hand, the '17,20,2l-bis-methylenedioxy derivatives actually convert the ketone to a non-reactive derivative. When both a 16u-hydroxy and l7a-hydroxy substituent are present, these groups can be protected via formation of a l6a,17a-acetal or ketal. The various protecting groups mentioned above can be removed by means known per se, for example, by mild acid hydrolysis.

In compounds wherein there is present neither a 17cchydroxy nor 21-hydroxy substituent but there is present a 20-oxo group, the 20-oxo group can be protected via reduction to the corresponding carbinol (hydroxy) group. Thus, for example, the l7-acetyl side chan can be protected via conversion to a l7-(a-hydroxyethyD-side chain. Regeneration of the 17acetyl side chain can be simply elfected via conventional oxidation means, for example, via oxidation with chromium trioxide in an organic solvent such as glacial acetic acid. Similarly in compounds containing a 17-oxo, this group can be protected by reduction to the corresponding carbinol (hydroxy) group. Thus, the 17-oxo group can be reduced to a 17fi-OH, 17oz-H moiety, from which, when desired, the 17-oxo moiety can be regenerated by oxidation, as described above. Furthermore, a ZO-hydroxy or 17,8-hydroxy group, can itself be protected by esterification, for example, with a lower alkanoic acid such as acetic acid, caproic acid, or the like; or by etherification with moieties such as tetrahydropyranyl, benzyl, benzhdryl, trityl, allyl, or the like.

The 16a,17a or l7a,21-acetals and ketals above discussed can be formed by reacting 16oz, 17a-bis-hydroxy or 17a,21-bis-hydroxy starting materials with an aldehyde or a ketone; preferably it is done by reacting a simple acetal or ketal (i.e. a lower alkylene glycol acetal or ketal of a suitable aldheyde or ketone) with the moieties sought to be protected.

Suitable aldehydes and ketones include lower alkanals of at least two carbon atoms, such as paraldehyde, propanal and hexanal; di(lower alkyl) ketones, such as acetone, diethylketone, dibutylketone, methylethylketone, and methylisobutylketone; cycloalkanones, such as cyclobutanone, cyclopentanone and cyclohexanone; cycloalkyl (lower alkanals), such as cyclopentylcarboxaldehyde and cyclohexylcarboxaldehyde; cycloalkyl lower alkyl ketones, such as cyclopentyl propyl ketone, cyclohexylmethyl ethyl ketone; dicycloalkyl ketones, such as dicyclopentyl ketone, dicyclohexyl ketone and cyclopentyl cyclohexyl ketone; cycloalkyl monocyclic aromatic ketones, such as cyclohexyl p-chlorophenyl ketone, cyclopentyl o-methoxyphenyl ketone, cyclopentyl o,p-dihydroxy-phenyl ketone and cyclohexyl m-tolyl ketone; cycloalkyl-lower alkyl monocyclic aromatic ketones, such as cyclopentylmethyl phenyl ketone; cycloalkyl monocyclic aromatic-lower alkyl ketones, such as cyclopentyl benzyl ketone and cyclohexyl phenethyl ketone; cycloalkyl-lower alkyl monocyclic aromatic-lower alkyl ketones, such as cyclopentylmethyl benzyl ketone; halo-lower alkanals, such as chloral hydrate, trifiuoroacetaldehyde hemiacetal, and heptafluorobutanal ethyl hemiacetal; halo-lower alkanones, such as 1,1,1-trifiuoroacetone; monocyclic carbocyclic aromatic aldehydes, such as benzaldehyde, halobenzaldehydes (e.g. pchlorobenzaldehyde and p-fluorobenzaldehyde), lower alkoxy-benzaldehydes (e.g. o-anisaldehyde), di(lower alkoxy)benzaldehydes (e.g. veratraldehyde), hydroxybenzaldehydes (e.g. salicylaldehyde), lower alkyl benzaldehydes (e.g. m-tolualdehyde and p-ethylbenzaldehyde), di (lower alkyl)-benzaldehydes (e.g. o-p-dimethylbenzaldehyde); monocyclic carboxylic aromatic lower alkanals, such as phenylacetaldehyde, u-phenylpropionaldehyde, B- phenylpropionaldehyde, 4-phenylbutyraldehyde, and aromatically-substituted halo, lower alkoxy, hydroxy and lower alkyl cyano derivatives thereof; monocyclic carbocyclic aromatic ketones, such as acetophenone, a,u,a-trifiu0- roacetophenone, propiophenone, butyrophenone, valerophenone, halophenyl lower alkyl ketones (e.g. p-chloroacetophenone and p-chloropropiophenone); (lower alkoxy) phenyl lower alkyl ketones (e.g. p-anisyl methyl ketone); di-(lower alkoxy) phenyl lower alkyl ketones; hydroxy-phenyl lower alkyl ketones; (lower alkyl)phenyl lower alkyl ketones (e.g. methyl p-tolyl ketone); di(lower alkyl) phenyl lower alkyl ketones (o,p-xylyl methyl ketone; benzophenone, and mono-or bis-substituted halo, lower alkoxy, hydroxy and lower alkyl derivatives thereof; monocyclic carbocyclic aromatic lower alkanones, such as 1-phenyl-3-butanone and 1-phenyl-4-pentanone, and aromatically substituted derivatives thereof.

Especially suitable are those aldehydes or ketones which, with the 16a,17uor 17a,21-bis-hydroxy grouping form an acetal or ketal group of the formula wherein P is individually selected from the group consisting of hydrogen and lower alkyl; Q is individually selected from the group consisting of lower alkyl and aryl; and P and Q taken together are lower alkylene.

The term lower alkylene comprehends polymethylene chains such as tetramethylene and pentamethylene.

In discussing the various starting materials, intermediates and end-products of this invention, the various protecting groups discussed above will not necessarily be specifically mentioned, but it should be understood that mention of any substituent comprehends the various protected forms thereof, unless specifically mentioned to the contrary.

In one embodiment of this invention, compounds of Formula I through V are prepared from 9,8,1019-androstan-S-ones or 95,lOfl-desA-pregnan-S-ones of the formula.

X VI

wherein X has the same meaning as above and D represents the carbon and hydrogen atoms necessary to complete the steroid D-ring, as well as the atoms in the substituents in the 16- and 17-positions, as defined in Formulae I-V above.

Thus, 9/8,10a-androstanes of Formula I can be prepared from 9,8,10,8-desA-androstan--ones of the formula (VII) wherein R R R and X have the same meaning as above.

Similarly, 9fl,10ot-androstanes of Formula II can be prepared from 9/3,IOB-desA-androstan-S-ones of Formula VIII and 9b,10o-androstanes of Formula III from 95,103- desA-androstan-S-ones of Formula IX.

/ I -10wer alkenyl wherei 1, R and X have the same meanin as above.

(VIII) Moreover, 9p,10et,17,8-pregnanes of Formulae IV and V can be prepared from 95, l0fi-desA-pregnan-5-ones of Formulae X and XI, respectively.

wherein R';,, R R and X have the same meaning as above.

The conversion of a 9 3,10fi-desA-compound of Formu la VI to a 93,10a-ster0id of Formula I-V (i.e., VH- I, VIII- 11, IX III, XeIV and XI- V) is eifected by condensing the 95,10fi-desA-compound with a compound selected from the group consisting of lower alkyl vinyl ketone (as well as substitutes therefor such as l-tertiary amino-3-butanone, l-tertiary amino-3-pentanone and quaternary ammonium salts thereof), 1,3-dichlorobut-2-ene, 1,3-dichloropent-2-ene, 1-Q-butan-3-one, 1-Q-butan-3-one lower alkylene ketal, 1-Q-butan-3-ol, 1-Q-butan-3-ol ether, esterified l-Q-butan-S-ol, l-Q-pentan-S-one, l-Q-pentan- 3-one lower alkylene ketal, l-Q-pentan-S-ol, l-Q-pentan-3-ol ether or esterified 1-Q-pentan-3-ol. Q is bromo, chloro or iodo, with the former two being preferred. Methyl vinyl ketone and l-tertiary amino-S-butanone are the preferred reagents, and the former is especially preferred. Prior to the condensation it is desirable to protect the 20-keto group present in compounds of Formulae X and XI, then it is not necessary to protect 16a,17ot or 21-hydroxy groups which are present, but groups protecting these moieties can be retained through the condensation reaction.

The above indicated substitutes for lower alkyl vinyl ketones are compounds wherein the vinyl moiety is re placed by a moiety of the formula wherein each R is lower alkyl or taken together both Rs are lower alkylene, oXa-lower alkylene or aZa-lower alkylene. Such moieties are, for example, dimethylamino, diethylamino, pyrrolidino, piperidino, morpholino, or the like. The quanternary ammonium salts thereof are formed via the utilization of conventional quaternizing agents, for example, lower alkyl or phenyl-lower alkyl (especially benzyl) halides, mesylates or tosylates.

When a lower alkyl vinyl ketone or substitute therefor, l-Q-butan-3-one or l-Q-pentan-S-one is used as the reaction partner for the condensation, ring closure to ring A (containing a 3-oxo moiety) of the desired 95,10a-ster0id of Formulae I-V occurs simultaneously with the condensation. However, when 1,3-dichlorobut-2-ene, 1,3-dichloropent-Z-ene, 1-Q-butan-3- lower alkylene ketal, l-Q-butan- 3-01, l-Q-butan-3-ol ether, esterified 1-Q-butan-3-ol, 1-Q- pentan-3-one lower alkylene ketal, 1-Q-pentan-3-ol, l-Q- pentan-3-01 ether, or esterified 1-Q-pentan-3-ol is used as the reaction partner a subsequent step to generate the 3- oxo moiety is required. When 1-Q-butan-3-ol or l-Q- pentan-3-ol is used as the reaction partner, the oxo moiety can be generated by oxidation and for this purpose, it is suitable to use oxidation means known per se, for example, chromic acid, chromium trioxide in acetic acid or the like. When esterified or etherified 1-Q-butan-3-ol or esterified or etherified 1-Q-pentan-3-ol is used as the reaction partner, hydrolysis of the esterified or etherified hydroxy group should be effected prior to oxidation. Suitable ester forming moieties are, for example, carboxylic acids, e.g. lower alkanoic acid such as acetic acid, benzoic acid, and the like; and hydrolysis of the reaction products obtained by reacting such 1-Q-butan-3-ol or l-Q-pentan-3-ol esters is suitably conducted by alkaline hydrolysis, e.g., via the use of an aqueous alkali metal hydroxide such as aqueous sodium hydroxide. Suitable ethers are, for example, lower alkyl ethers, i.e. 3-methoxy, 3-ethoxy or the like; and these are suitably hydrolyzed by acid hydrolysis, e.g. via the use of an aqueous mineral acid such as hydrochloric acid, sulfuric acid or the like. When a l-Q-butan-3-one lower alkylene ketal or a l-Q-pentan-3-one lower alkylene ketal is used as the reaction partner, mild acid hydrolysis of the ketal moiety results in generation of the 3-oxo moiety. Finally, when 1,3 dichlorobut-3-ene or 1,3-dichloropent-3-ene is used as the reaction partner, the 3-oxo moiety can be generated by treatment with a concentrated mineral acid, preferably a strong acid such as hydrochloric acid or sulfuric acid. It should be noted, that 1,3-dichlorobut-Z-ene and 1,3-dichloropent-2-ene may be used as reaction partners with compounds of Formulae X and XI, but not with the 17a-lower alkyl, alkenyl or alkynyl compounds of Formulae VIII-D(. As will be apparent, when a reaction partner based on butane (i.e. having a four carbon atom skeleton) is utilized a compound of Formulae I-V wherein Y is hydrogen is obtained. Similarly, when a reaction partner based on pentane is utilized a compound of Formulae I-V wherein Y is methyl is obtained.

In addition to the preparation of compounds of Formulae I-V from compounds of Formulae VI-XI by the use of the above mentioned reaction partners, it is also possible by the procedures of this invention to prepare compounds of Formulae I-V which, in the A-ring, in addition to containing an unsaturation between the 4- and S-positions also contain an unsaturation between the 1- and 2-positions. Such l,4-diene products corresponding to the compounds of Formulae I-V can be prepared from compounds of Formulae VI-XI by condensation of the latter with a reaction partner selected from the group consisting of ethinyl methyl ketone and ethinyl etheyl ketone (as well as substitutes therefor such as fi-tertiary amino-vinyl methyl or ethyl ketone, quaternary ammonium salts thereof, and B-lower alkoxy-vinyl methyl or ethyl ketone) Condensation to prepare such a 1,4-diene product corresponding to the compounds of Formulae I-V is effected under the same conditions as is the condensation to prepare a compound of Formulae I-V. The so-obtained 1,4-dienes are useful in the same way as the correspondingly substituted 4-ene-compounds of Formulae I-V.

The condensation is suitably effected at, below or above room temperature. For example, at the reflux temperature of the reaction medium or at ice temperature C.) or 'below. Moreover, the condensation is suitably effected in an organic medium. Preferably the solvent is a lower alkanol, such as methanol, isopropanol, tert-butanol, ethanol, or another non-ketonic organic solvent such as an ether, e.g. dioxane, diethyl ether, diisopropyl ether, aromatic hydrocarbon, e.g. benzene, toluene, xylene, organic acid, such as acetic acid, or the like. Lower alkanols are the preferred solvents. It is suitable to catalyze the condensation, and this can be effected via use of a catalyst such as an alkali metal lower alkoxide, for example sodium ethoxide, potassium t-butoxide, sodium t-amylate, or the like, alkali metal hydroxide such as sodium, lithium or potassium hydroxide, a quaternary ammonium hydroxide, for example, a benzyl tri-lower alkyl ammonium hydroxide such as benzyl trimethyl ammonium hydroxide, para-toluene sulfonic acid, or the like.

When using a substitute for methyl or ethyl vinyl 5 ketone, or for methyl or ethyl ethinyl ketone, the condensation should be effected under alkaline conditions. As indicated above, among such substitutes are l-tertiary amino-3-butanone, l-tertiary amino-3-pentanone and B- tertiary amino-vinyl methyl or ethyl ketone. Preferred tertiary amino groups are dilower alkylamino groups such as dimethylamino, diethylamino, pyrrolidino, piperidino, morpholino, or the like. Preferred quaternary ammonium salts of such tertiary amino groups are, for example, those formed from lower alkyl halides such as methyl iodide. An exemplary B-lower alkoxy vinyl methyl or ethyl ketone is fl-methoxyvinyl ethyl ketone.

One aspect of this invention is the hydrogenation of desA-androst 9-en-5-ones or desA-pregn-9-en-5-ones to 9,8,IO/S-desA-androstan-S-ones of Formulae VII'D( or to 93,10,8-desA-pregnan-5-ones of Formulae XX'I. Thus, 9B,lOfi-desA-androstan-S-ones of Formula VII can be prepared via hydrogenation of desA-androst-9-en-5-ones of the formulae H 30 Raf X (XII) HaC R l --l0wer alkenyl R:

x (XIII) --lower alkynyl MNR H X (XIV) wherein R R R and X have the same meaning as above,

particularly a compound in accordance with this invention, having the formula:

11 CH3 l ts H X (XII-A) wherein R is hydroxy, lower alkanoyloxy, carboxyloweralkanoyloxy, benzoyloxy, tetrahydropyranyloxy, benzyloxy, benzhydryloxy, trityloxy, allyloxy, or lower alkoxy-lower alkoxy; R is hydrogen or lower alkyl; R and R taken together are selected from the group consisting of (175-011, l7a-lower alkanoic acid lactone) lower alkylenedioxy and oxo; R is hydrogen, lower alkyl, hydroxy, lower alkanoyloxy, carboxyloweralkanoyloxy, benzoyloxy, tetrahydropyranyloxy, benzyloxy, benzhydryloxy, trityloxy, allyloxy or lower alkoxylower alkoxy; and X is as above.

Also, 95,lQB-desA-pregnan-S-ones of Formulae X and XI can be prepared by hydrogenation of desA-pregn-9- en-S-ones of the formulae X (XVI) wherein R';,, R R and X have the same meaning as above,

particularly a compound in accordance with this invenvention, having the formula:

wherein R is hydrogen, halogen, lower alkyl, hydroxy,

lower alkanoyloxy, carboxyloweralkanoyloxy, benzoyloxy, tetrahydropyranyloxy, benzyloxy, benzhydryloxy, trityloxy, allyloxy or lower alkoxy-lower alkoxy; R' is hydrogen, lower alkyl, fluoro, hydroxy, lower alkanoyloxy, carboxyloweralkanoyloxy, benzoyloxy, tetrahydropyranyloxy, benzyloxy, benzhydryloxy, trityloxy, allyloxy or lower alkoxy-lower alkoxy; R is hydrogen, halogen, hydroxy, lower alkanoyloxy, carboxyloweralkanoyloxy, benzoyloxy, tetrahydropyranyloxy, benzyloxy, benzhydryloxy, trityloxy, allyloxy or lower alkoxy-lower alkoxy; X is as above; R is individually hydroxy, lower alkanoyloxy, carboxyloweralkanoyloxy, benzoyloxy, tetrahydropyranyloxy, benzyloxy, benzhydryloxy, trityloxy, allyloxy or lower alkoxy-lower alkoxy; and R is individually hydrogen or, taken together with R 0x0 or lower alkylenedioxy; or R and R taken together form a ketal or acetal of a lower alkanal containing at least two carbon atoms, a di(loweralkyl) ketone, a cycloalkanone con taining from 4 to 6 carbon atoms, a (cycloalkyl con taining from 4 to 6 carbon atoms) lower alkanal, a (cycloalkyl containing from 4 to 6 carbon atoms) lower alkanone, a dicycloalkyl ketone containing from 11 to 13 carbon atoms, a phenyl lower alkanone, or benzophenone; or R R and R taken together from a bis-methylenedioxy; or R' and R taken together from a ketal or acetal of a lower alkanal containing at least two carbon atoms, a di(loweralkyl) ketone, a cycloalkanone containing from 4 to 6 carbon atoms, a (cyeloalkyl containing from 4 to 6 carbon atoms) lower alkanal, a (cycloalkyl containing from 4 to 6 carbon atoms) lower alkanone, a dicycloalkyl ketone containing from 11 to 13 carbon atoms,

a phenyl lower alkanone, or benzophenone.

Prior to hydrogenation, the 0-20 keto group in compounds of Formulae XV and XVI or 0-17 keto group in compounds of Formula XII should be protected either by conversion to the corresponding carbinol or by ketalization as described above. The hydrogenation can, however, be effected without protecting such keto groups.

Moreover, it should be noted that the hydrogenation, besides inserting a hydrogen atom in each of the 9- and 10-positions, can also simultaneously efr'ect hydrogenation of other groups in the molecule. For example, the C-20-keto group can be hydrogenated to the corresponding carbinol or the C-17 lower alkenyl group in compounds of Formula XIII or the C-l7 lower alkynyl group in compounds of Formula XIV can be hydrogenated to the corresponding C-17-lower alkyl compounds. Compounds of Formulae VIII and IX can, in turn, be prepared from compounds of Formula VII wherein R and R together are oxo via reaction with a lower alkenyl or lower alkynyl Grignard reagent, with prior protection of the S-keto group, for example, by forming S-ketals without concurrent blocking of the 17-keto group. In the same manner compounds of Formulae XIII and XIV can be formed from compounds of Formula XII wherein R and R taken together are oxo.

The hydrogenation of desA-androst-9-en-5-ones of Formulae XII-XIV and of desA-pregn-9-en-5-ones of Formulae XV-XVI is one of the main features of this invention. It is effected by catalytic hydrogenation, suitably using a precious metal catalyst. Suitable precious metal catalysts are palladium, platinum, ruthenium, and rhodium, the latter two being especially preferred. It is particularly advantageous to use rhodium, for example, rhodium on charcoal (or carbon powder, carbon black, or the like) or rhodium on alumina. In contrast to what would be expected, it has been found that such a catalytic hydrogenation of a compound of Formulae XII- XVI gives a substantial yield of a compound of Formulae VI-XI. In fact, it has been found that such catalytic hydrogenation gives a major proportion of a compound of the Formulae VI-XI. This catalytic hydrogenation is suitably effected in an inert organic solvent, for example, a lower alkanol such as methanol or ethanol, an ether such as dioxane or diglyme, a hydrocarbon such as cyclohexane, hexane, or the like. Lower alkanols are preferred solvents. Moreover, it is suitably conducted in the presence of an acidic or basic catalyst, for example, an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide or the like, or a mineral acid, for example, a hydrohalic acid, such as hydrochloric acid, or the like, or an organic acid such as a lower alkanoic acid, for example, acetic acid. The reaction can be conducted at, above or below room temperature, for example, from about 5 C. to about C. However, it is preferably conducted at a temperature between about 0 C. and about 35 C.

As described above, the desA-androst-9-ene-5-ones or desA-l7/3-pregn-9-en-5-ones of Formulae XII-XVI can be prepared from natural steroids by a variety of methods. Thus, in one embodiment of this invention said desA- androst-9-en-5-ones or desA-17fi-pregn-9-en-5-ones can be prepared from steroids of the 3-oxoandrost-4ene or 3-oxo-l7 3-pregn-4-ene series by a reaction sequence which involves as a first step an oxidative ring opening of ring A of the natural steroid. For this oxidative ring opening there can be used as starting materials, natural steroids of the 3-oxo-androst-4-ene or 3-oxo-17p3-pregn-4-ene series of the formula:

(XVII) The oxidative ring opening of a natural steroid of Formula XVII yields a 5-oxo-3,5-seco-A-norandrostan-3-oic acid or a 5-oxo-3,5-seco-A-norpregnan-3-oic acid of the formula I H3O B f i H00 ,kx

wherein X and Z have the same meaning as above. The oxidative ring opening of the compound of Formula XVII can be performed by a variety of methods. In a preferred embodiment it is effected by ozonolysis. The ozonolysis is suitably carried out in an organic solvent, for example, acetic acid, ethyl acetate, methanol, chloroform, methylene chloride, or the like, or a mixture of two or more of such solvents such as ethyl acetate/ acetic acid, ethyl acetate/methylene chloride, or the like. Moreover, the ozonolysis is advantageously conducted at below room temperature. Thus, it is preferably conducted at a temperature between about 70 C. and about 25 C. The resulting ozonides can be decomposed by conventional means, for example, by treatment with, hydrogen peroxide in water, acetic acid or ethyl acetate, or the like. The oxidative ring opening of a compound of Formula XVII to a compound of Formula XVIII can also be effected by other oxidation means, for example, by treatment with hydrogen peroxide. It should be noted that an oxidative ring opening by either ozonolysis or by treatment with hydrogen peroxide, does not require protection of any of the substituents at C-l6 or C-17. However, as stated above, it may be desirable to protect these substituents against some subsequent reaction in the total reaction sequence being practiced. On the other hand, the oxidative ring opening can also be effected by oxidation with chromium trioxide or via treatment with sodium periodate and potassium permanganate in potassium carbonate solution and if these oxidation means are used, it is necessary to protect any secondary hydroxy groups which might be present such as a 16,175- or 21-hydroxy group; preferably, for the purpose of this reaction, with non-aromatic protecting groups.

Following the oxidative ring opening of the A-ring, the

XVIII so-obtained 5-oxo-3,5-seco-A-norandrostan-3-oic acid or 14 5-oxo-3,5-seco-A-norpregnan-3-oic acid of Formula XVIII is converted into a mixture of a 10a-desA-androstan-S-one and a IOB-desA-androstan-S-one or a mixture of a 10a-desA-pregnan-5-one and a 10l3-desA-pregnan-5- one as illustrated below:

1150 XVIII l H i /i i alkali metal salt of XVII i0" 1 1 H XIX wherein in Formulae XD( and XX, X and Z have the same meaning as above.

The compounds of Formula XIX are l0a-desA-androstan- 5-ones or l0m-desA-pregnan-5-ones, depending on the meaning of Z, and the compounds of Formula XX are 1OB-dcsA-andrOstan-S-Ohes or 10fi-desA-pregnan-5-ones. The conversion of a compound of Formula XVIII into the compounds of Formulae XIX and XX is effected by pyrolysis. In effecting the pyrolysis, it is desirable to convert the 3-oic acid of Formula XVIII into a corresponding metal salt, for example, an alkali metal salt such as the sodium or lithium salt. This conversion to a metal salt can be effected prior to pyrolysis, e.g., by treating the acid with sodium hydroxide or in situ during the course of the pyrolysis, e.g., by fusing the 3-oic acid with a mixture of sodium acetate and potassium acetate. The pyrolysis can be conducted at atmospheric pressure or in a vacuum. One preferable embodiment is to conduct the pyrolysis in a vacuum, at a temperature from about 200 C. to about 350 C. in the presence of a proton acceptor, e.g. an alkali metal or alkaline earth metal salt of a weak organic acid, for example, potassium acetate, sodium acetate, sodium phenyl-acetate, sodium bicarbonate, or the like; especially preferred is a vacuum of from about .001 to about .5 mm. Hg. Accordingly, it is advantageous to conduct the pyrolysis under alkaline conditions, i.e. at a pH greater than 7. The pyrolysis can be effected in solution or by fusion. An especially preferred method of effecting the pyrolysis is by fusion of an alkali metal salt of a weak acid, for example, an organic carboxylic acid such as a lower alkanoic acid or a phenyl-lower alkanoic acid such as phenyl-acetic acid. Another method of effecting the pyrolysis is to heat, preferably at atmospheric pressure, a solution of an alkali metal salt, such as the sodium or lithium salt, of a 3-oic acid of Formula XVIII in a basic organic solvent. The basic organic solvent should, of course, be one which is in the liquid state at the temperature at which the pyrolysis is effected. Thus, the pyrolysis can be effected at a temperature up to the boiling point of the basic organic solvent being used. Suitable basic organic solvents are, for example, nitrogen containing organic solvents such as piperidine, pyridine, isoquinoline, quinoline, triethanolamine, or the like. When utilizing this approach using a basic organic solvent it is suitable to heat to temperature between about 200 C. and about 300 C., and preferably between about 230 C. and about 260 C. A preferred basic organic solvent for the pyrolysis of a salt of a compound of Formula XVIII to compounds of Formulae XIX and XX is quinoline. If a basic organic solvent is used which boils substantially below 200 C. at atmospheric pressure, it is suitable to conduct the pyrolysis in a sealed tube or an autoclave.

In another aspect, compounds of Formula XIX can be prepared from compounds of the formula (XIX-A) wherein X and Z have the same meaning as above.

The compounds of Formula XIX can be prepared from compounds of Formula XIX-A in the same manner that compounds of Formula XIX are prepared from compounds of Formula XVII, i.e. by oxidative ring opening of the A-ring of a compound of Formula XIXA followed by elimination of the residue of the A-ring, to yield a compound of Formula XIX. The oxidative ring opening of the compound of XIX-A can be performed by ozonoylsis as described above for the conversion of a compound of Formula XVII to a compound of Formula XVIII. Such ozonolysis of a compound of Formula XIX-A yields a compound of the formula (XIX-B) wherein X and Z have the same meaning as above, and A is carboxy or formyl.

A compound of Formula XIXB can then be converted to a compound of Formula XIX. This removal of the residue of the A-ring, i.e. decarboxyl-ation Ianrd deformylation can be eflected by heating in an acidic or basic medium. It is preferred to heat to the reflux temperature of the medium which is preferably an inert organic solvent such as a lower alkanol, e.g. ethanol, dioxane, ether or the like. The decarboxylation and deformylation yields mainly a compound of Formula XIX, but also a minor yield of the corresponding IOB-isomer of Formula XX.

Compounds of Formula XIX can also be formed from a compound of Formula XVIII via the formation of an enol-lactone of a compound of Formula XVIII, i.e. via the formation of a 4-oxo-androst-5-en-3-one or a 4-oxopregn-5-en-3-one of the formula:

(XXI) wherein X and Z have the same meaning as above, which can then be reacted with a Grignard reagent, such as phenyl magnesium bromide or phenyl lithium, to form the resulting aldol of, for example, the formula (XXII) wherein X and Z have the same meaning as above,

which, upon treatment with an alkali metal hydroxide, such as potassium hydroxide, at an elevated temperature, for example, from about 200 C. to about 240 C., is converted to the corresponding 10a-desA-androstan-5-one or IOu-desA-pregn-S-One of Formula XIX.

It should be noted that though the pyrolysis of a compound of Formula XVIII yields both the 10,8-cornpounds of Formula XX and the Illa-compounds of Formula XIX, and though either of these isomers can be used in the subsequent halogenation and dehydro-halogenation steps of this reaction sequence, it is sometimes preferable to convert the 10fl-compound of Formula XX into the corresponding IOOL-COHIPOLlDd of Formula XIX. This conversion can be effected by treating a 10,8-desA-androstan-5- one or 10/i-desA-pregnan-5-one of Formula XX with any base capable of producing a carbanion; for example, it is suitable to use an alkali metal lower alkoxide in an organic solvent such as a lower alkanol, for example, sodium ethoxide in an ethanol solution or sodium methoxide in a methanol solution.

The above-discussed conversion via the alkali metal salt and pyrolysis of compounds of Formula XVIII to compounds of Formulas XIX and XX can be eifected without protection of any of the substituents which might be present at 0-16 or C-17. However, if it is desired for either preceding or succeeding reaction steps of the total reaction sequence, the conversion of a compound of Formula XVIII to compounds of Formulas XIX and XX can be effected with protecting groups present on substituents in the C-16 or C-17 position.

As stated above, the 1Oa-desA-andIostan-S-Qnes or 10adesA-pregnan-S-ones of Formula XIX or the 10,8-desA- androstan-S-ones of 10,8-desA-pregnan-5-ones of Formula XX can be converted via a two-step sequence of halogenation and dehydrohalogenation into the desired starting material desA-androst-9-en-5-one or desA-pregn-9-en- 5-one of Formulas XII, XV, and XVI.

In a preferred embodiment a lOa-desA-andrOstan-S-One or a 10a-desA-pregnan-5-one of Formula XIX is subjected to the two-step sequence of halogenation and dehydrohalogenation. Halogenation of a compound of Formula XIX or a compound of Formula XX yields a mixture of corresponding halogenated compounds including one of the formula X (XXIII) wherein X and Z have the same meaning as above, and

Hal is a halogen atom (preferably Br or Cl),

XV and XVI. Keto groups except for the S-keto group, may require protection prior to the halogenation. In the case of compounds of Formulas XIX and XX containing the C-l7 dihydroxyacetone side chain, represented in Formula V wherein R is hydroxy, this protection can be etfected by formation of the 17u,20;20,2l-bis-methylenedioxy derivative. In other cases wherein a -17 0x0 or C-20 oxo group is present, protection can be efiected by reduction to the corresponding carbinol either directly prior to the halogenation step or prior to some other step in the reaction sequence leading to the compounds of Formulas XIX and XX.

The halogenation can be effected with halogenating agents such as bromine, sulfuryl chloride, or the like. Bromination is especially preferred. The bromination is suitably effected by treatment with bromine at room temperature or below, preferably at ice temperature or below. Suitably it is conducted in an organic medium; for example, an organic acid such as acetic acid; an ether such as an anhydrous ether, dioxane, tetrahydrofuran; a chlorinated organic solvent such as methylene chloride, chloroform, carbon tetrachloride; or the like; with the addition of hydrogen bromide as a catalyst. When effecting halogenation with sulfuryl chloride, it is suitable to use the same type of organic medium as when brominating; and suitable catalysts are, for example, acetic acid, benzoyl peroxide, or the like.

The subsequent dehydrohalogenation of a compound of Formula XXIII is preferably conducted under mild dehydrohalogenating conditions; for example, by the use of an alkali metal carbonate (e.g. lithium carbonate) or an alkali metal halogenide (e.g. a lithium halide) in an organic solvent such as a di-lower alkyl-formamide, or with an organic base such as collidine, pyridine, or the like. The dehydrohalogenation is advantageously conducted at slightly elevated temperatures, for example, from about 50 C. to about 150 C., preferably from about 80 C. to about 120 C.

Separation of the desired product desA-androst-9-en- -one or desA-pregn-9-en-5-one of Formulas XII, XV .and XVI can be etfected by conventional means. As indicated above the halogenation procedure may result in halogenated by-products in addition to the desired intermediate of Formula XXIII. Accordingly, the separation is preferably effected after first subjecting the reaction mixture to dehalogenating conditions in order to dehalogenate the halogenated by-products formed by the halogenation procedure, but not dehalogenated by the dehydrohalogenation. Following such dehalogenation the reaction mixture can then easily be separated by conventional means, for example, by column chromatography, to yield the desired compound of Formulas XII, XV, XVI. An exemplary dehalogenation means is treatment with zinc and sodium acetate in an acetic acid solution at an elevated temperature, for example, about 80 C.

In the case of compounds of Formulas XIX or XX which contain a halogen atom on a carbon atom directly adjacent to a keto group, it is preferable to protect such a halogen atom against dehalogenation prior to subjecting the compound of Formulas XIX or XX to the two step sequence of halogenation and dehydrohalogenation of this embodiment. Such a grouping, containing a halogen atom on a carbon atom directly adjacent to a keto group, is illustrated in a compound of Formulas IV or V wherein R or R is halogen. Thus, if 10aor l0-fl-desA-pregnan- 5-one of Formulas XIX or XX containing a 1711- or 21- halo substituent is to be subjected to the halogenation dehydrohalogenation sequence it is desirable to first effect protection of the 1711- or 2l-halo substituent. This protection can be effected, for example, by ketalization of the -oxo group.

As stated above, the desired desA-androst-9-en-S-ones or desA-pregn-9-en-5-ones starting materials can also be prepared from steroids of the 3-oxo-androst-4-ene or 3- 18 oxo-l7fl-pregn-4-ene series containing an ll-hydroxy sub stituent. In one embodiment an ll-hydroxy steroid of the formula I H0 HE C HaC H Z I i t. H

X (XXIV) wherein X and Z have the same meaning as above,

is reacted with an acid or a reactive derivative thereof to form a leaving group in the ll-position. By reactive dereviative is meant, for example, a halide, e.g. a chloride, an anhydride, or the like. Through either or llahydroxy starting materials can be used, it is preferable to utilize a-hydroxy compounds of Formula XXIV as starting materials. Prior to the esterification reaction, it is preferable to protect hydroxy groups present in the C-l6, C-l7, or C-2l position. Suitable acids for the esterification of the ll-hydroxy group, which can be used to form a leaving group in the ll-position are organic acids such as phosphoric acid, organic carboxylic acids such anthraquinone [i-carboxylic acid or organic sulfonic acids, for example, toluene-sulfonic acids, especially p-toluene sulfonic acid, lower alkyl-sulfonic acids such as methanesulfonic acid and nitrophenyl-sulfonic acids, especially p-nitrophenylsulfonic acid. Especially preferred as the leaving group in the ll-position is a lower alkylsulfonyloxy group such as the mesoxy group. However, when it is desired to react a compound of Formula XXIV with a sulfonyloxy forming moiety, then a compound of Formula XXIV having an lie-configuration should be used as a starting material. The above described esterification of ll-hydroxy steroid starting materials of Formula XXIV yields compounds of the formulaxxv (XXVI) wherein X, Z and LO have the same meaning as above, particularly a compound in accordance with this invention selected from the group consisting of compounds of the formulae:

(XXVLD) and (XXVI-C) wherein 7 a, 11 12 13 'is 15 and R16 are as above; and L is toluene sulfonate, lower alkyl sulfonate or nitrophenyl sulfonate.

The oxidative ring opening of the A-ring of a compound of Formula XXV to a compound of Formula XXVI can be effected by ozonolysis as described above for the oxidative ring opening of the A-ring of a compound of Formula XVII to a compound of Formula XVIII. Pyrolysis of the so-formed compound of Formula XXVI under the conditions described above for the pyrolysis of a compound of Formula XVHI to compounds of the Formulas XD( and XX directly yields the desired desA-androst-9- en-S-one or desA-pregn-9-en-5-one of Formulas XII, XV, XVI. Thus, pyrolysis of a compound of Formula XXVI directly results in elimination of the leaving group in the ll-position as well as splitting off of the residue of ring A attached to the -position. This procedure of starting from an ll-hydroxy steroid (preferably lla-hydroxy) of Formula XXIV and proceeding through intermediates of Formulas XXV and XXVI to compounds of Formulas XII, XV, XVI, represents a particularly elegant procedure for preparing the latter compounds. An especially preferred method of effecting the pyrolysis of a salt of a 3-oic acid of Formula XVI is the method described above wherein the salt of the 3-oic acid is heated in a liquid basic organic solvent. Especially preferred solvents for the pyrolysis of a salt of a compound of Formula XXVI are triethanolamine and quinoline.

As indicated in the foregoing paragraph the pyrolysis of a salt of a compound of Formula XXVI involves two separate chemical attacks; one being the elimination of the 11 leaving group and the other being the splitting off of the A-ring residue. Instead of effecting these two attacks simultaneously, as described above, it is also possible to effect them sequentially by just prior to formation of the salt, effecting elimination of the leaving group of the compound of Formula XXVI. This elimination yields a A -seco acid of the formula H30 I H Z J x (XXVI-A) wherein X and Z have the same meaning as above,

particularly a compound in accordance with this invention selected from the group consisting of compounds of the formulae:

Rn CHz Ln MR1: H CH: 5\ /5 HO O C O X (XXVI-D) and (XXVIE) wherein 7 8, 11, 12, 13 '1s, 15 and R16 are as above.

The elimination can be effected by any conventional elimination means. It is suitably conducted under alkaline conditions in an anhydrous organic solvent. Preferably, it is effected by heating, i.e. at a temperature between about room temperature and the reflux temperature of the reaction mixture. Thus, treatment of a compound of Formula XXVI with either an inorganic or organic acid or base results in the formation of the desired compound of Formula XXVIA. Preferably a weak base is used, for example, a salt of a carboxylic acid (e.g. a lower alkanoic acid) with an alkali metal or an alkaline earth metal, for example, sodium acetate, potassium acetate, or the like. As indicated, the elimination is suitably conducted in an anhydrous organic solvent; suitable are solvents such as dilower alkyl-formamides, e.g. dimethylformamide, lower alkanoic acids, e.g. acetic acid, or the like. When a proton accepting solvent, such as dimethylformamide, is used, it itself can serve as the base for the purpose of this elimination reaction; i.e. if the solvent is basic then the elimination can be conducted without the addition of a separate basic material. Similarly, if the solvent is acidic, then the elimination can be conducted without the addition of a separate acidic material.

After the elimination is effected the A -seco acid product of Formula XXVI-A can then be converted to a salt, for example, an alkali metal salt, and the so-formed salt pyrolyzed according to the conditions described above for the pyrolysis of a compound of Formula XXVI to compounds of Formulas X II, XV and XVI.

After the above-dscribed ll-leaving group elimination and A-ring residue splitting, conducted either simultaneously or sequentially, the desired desA-9-en-5-one compounds of Formulas XII and XV and XVI can be isolated by conventional means. However, it has been found particularly suitable with compounds of Formulas XV and XVI to isolate by forming the disemicarbazone of the pyrolysis product and then regenerating therefrom the desired 5,20-dione of Formulas XV or XVI, or if the 20-oxo group has been protected, for example, by reduction to a 20-hydroxy moiety, by forming the semicarbazone at the 5-position and then regenerating therefrom the desired 5-one compound.

In yet another embodiment of this invention starting material ll-hydroxy steroids of Formula XXIV can be directly subjected to an oxidative ring opening of the A- ring by ozonolysis or treatment with hydroxide peroxide,

(XX VII) wherein X and Z have the same meaning as above particularly a compound in accordance with this invention selected from the group consisting of compounds of the formulae:

(XXVII-A) and (XXVII-B) Hi0 XXVII H P2 z alkali metal salt H30 2 HaCj H (XXVIII) (XXIX) wherein in Formulas XXVIII and XXIX, X and Z have the same meaning as above, particularly a compound 22 in accordance with this invention selected from the group consisting of compounds of the formulae:

(XXXIX-A) and (XXIX-B) wherein X, R7, R3, R11, R12, R13, R'13, R15 and R1 are as above.

This pyrolysis of an alkali metal salt derived from a compound of Formula XXVII can be effected under the same conditions as described above for the pyrolysis of a compound of Formula XVIII to compounds of the Formulae XIX and XX. Though either the IOB-compound of Formula XXVIII or the lOa-compound of Formula XXIX can be subjected to the subsequent steps of this reaction sequence, it is suitable to utilize the lOfl-compound of Formula XXVIII. Conversion of the loot-00mpound of Formula XXIX to the loft-compound of Formula XXVIII can be effected under the same conditions as described above for the conversion of the compound of Formula XX to a compound of Formula XIX.

In the next step of this reaction sequence, the 11-hydroxy compound of Formula XXVIII or of Formula XXIX can be subjected to esterification whereby to convert the ll-hydroxy group to a leaving group in the 11- position. This esterification can be effected with the same acids or acid derivatives and in the same manner as described above for the esterification of a compound of Formula XXIV to a compound of Formula XXV. As in that instance, it is also preferred in the present instance to form a mesoxy leaving group in the ll-position, though, of course, other leaving groups as described above are useful for the instant purpose. There is thus obtained a compound of the formula wherein X, Z and LO have the same meanings as above.

The leaving group can then be eliminated from the 11- position of a compound of Formula XXX resulting in a direct formation of a desA-audrost-9-en-5-one or a desA- pregn-Q-en-S-one of Formulae XII, XV, XVI. This elimination can be efl ected by any conventional elimination means. It is suitably conducted under alkaline conditions in an anhydrous organic solvent. Preferably, it is effected by heating, i.e. at a temperature between about room temperature and the reflux temperature of the reaction mixture. Thus, treatment of a compound of Formula XXX with either an inorganic or organic base results in the formation of the desired compound of Formulae XII, XV, XVI. Preferably a weak base is used, for example, a salt of a carboxylic acid (e.g. a lower alkanoic acid) with an alkali metal or an alkaline earth metal, for example, sodium acetate, potassium acetate, or the like. As indicated, the elimination is suitably conducted in an anhydrous organic solvent; suitable are solvents such as dilower alkyl-formamides, e.g. dimethyl formamide, lower alkanoic acids, e.g. acetic acid, or the like. When a proton accepting solvent, such as dimethyl formamide, is used, it itself can serve as the base for the purpose of this elimination reaction; i.e. if the solvent is basic then the eliminaton can be conducted wthout the addition of a separate basic material.

In another aspect, compounds of Formula XXX can be prepared from compounds of the formula wherein X, Z and LO have the same meanings as above.

The compounds of Formula XXXA can be prepared from corresponding ll-hydroxy compounds by esterification as described above for the preparation of compounds of Formula XXV from compounds of Formula XXIV. The compounds of Formula XXX can be prepared from compounds of Formula XXXA in the same manner that compounds of Formula XXX are prepared from compounds of Formula XXV, i.e. by oxidative ring opening of the A-ring of a compound of Formula XXXA followed by elimination of the residue of the A-ring to yield a compound of Formula XXX. The oxidative ring opening of the compounds of Formula XXXA can be performed by ozonolysis as described above for conversion of a compound of Formula XXV to a compound of Formula XXVI. Such ozonolysis of a compound of Formula XXXA yields a compound of the formula wherein X, Z and LO have the same meaning as above.

A compound of Formula XXX-B can then be converted to a compound of Formula XXX. This removal of the residue of the A-ring, i.e. decarboxylation, can be effected as described above for the conversion of a compound of Formula XIX-B to a compound of Formula XIX.

The compounds of Formulae I-V preparable by the methods of this invention are not only pharmaceutically useful compounds as described above, but also are themselves useful as intermediates for other 9,3,10a-steroids; for example, compounds wherein X is hydrogen or lower alkyl can be modified so as to introduce unsaturation between C-6 and -7. This can be effected by dehydrogenation means, for example, by halogenation followed by dehydrohalogenation or by means of 2,3-dichloro-5,6- dicyanobenzoquinone, according to known methods. Thus, for example, a 9fl,10u-progesterone of Formula IV wherein X is hydrogen or lower alkyl can be converted to a 9,8,10apregna-4,6-dien-3,20-dione.

(XXX-B) ably with a carboxylic acid, for example, a lower alkanoic acid such as acetic acid, benzoic acid, or the like. Conversion of the so-obtained ll-esterified hydroxy compound then yields an ll-(esterified hydroxy)-desA-androst-9-en-5-one (i.e. a compound of Formula XII containing an ll-esterified hydroxy moiety) or an ll-esterified hydroxy-desA-pregn-9-en-5-one (i.e. a compound of Formulae XV-XVI containing an lla-esterified hydroxy moiety). This conversion can be effected by halogenation followed by dehydrohalogenation, as described above for the conversion of a compound of Formula XIX or XX to a compound of Formula XII, XV or XVI. Catalytic hydrogenation of the so-obtained compound of the formula HaC X (XXXI) wherein X and Z have the same meaning as above, and E0 is an esterified hydroxy group as described above in this paragraph,

yields an ll-esterified hydroxy-desA-9/3,10fl-androstan-S- one or ll-esterified hydroxy-desA-9/3,10,6-pregnan-5-one,

of the formula III z i H HaC- V X (XXXII) wherein X, Z and E0 have the same meaning as above.

This hydrogenation can be conducted in the same manner as described above for the hydrogenation of a compound of Formulae XII-XVI to a compound of Formulae VII, X, XI. Also, compounds of Formula XXXII containing a 17-oxo moiety can be converted to a corresponding compound containing a l7B-hydroxy, 17a-lower alkenyl or lower alkynyl moiety by the methods described above. Also, compounds of Formula XXXII can be hydrolyzed to yield corresponding ll-hydroxy compounds of Formula XXXII, i.e. wherein E0 is hydroxy.

Condensation of the so-obtained compound of Formula XXXII or the corresponding 17fi-hydroxy, c-1OW61 alkenyl or lower alkynyl compound (i.e. a compound of Formula VI containing a free or ll-esterified hydroxy group) then yields the desired end-product 9,8,10a-steroid of Formulae I-V containing an ll-hydroxy group. Such condensation can be effected as described above for the preparation of a compound of Formulae I-V from a compound of Formulae VI-XI. The so-obtained 95,100:- steroids containing an ll-esterified hydroxy group can be hydrolyzed to the corresponding compounds containing 25 an ll-hydroxy group, which latter compounds are themselves llseful as intermediates, for example, the ll-hydroxy group can be oxidized by methods known per se to yield corresponding ll-oxo steroids analogous to compounds of Formulas I-V.

The pharmaceutically useful compounds prepared by the methods of this invention can be administered internally, for example, orally or parenterally, with dosage adjusted to individual requirements. They can be administered in conventional pharmaceutical forms, e.g. capsules, tablets, suspensions, solutions, or the like.

The following examples are illustrative but not limitative of this invention. All temperatures are in degrees centigrade. The Florisil adsorbent used infra is a synthetic magnesia-silica gel available from the Floridin Company, PO. Box 989, Tallahassee, Fla. (cf. p. 1590, Merck Index, 7th edition, 1960). 100-200 mesh material was used. The moiety designated by tetrahydropyranyloxy is tetrahydro-Z-pyranyloxy. When it is stated that a procedure is elfected in the cold, it should be understood that it is commenced at C. Throughout this application when compounds of the pregnane series are referred to it should be understood that it is compounds of the 17ppregnane series that are being referred to, unless specifically indicated to the contrary, and whether or not the compound of the pregnane series is specifically indicated as of the l7fl-series.

Example 1 A solution of 3.2 g. of 17a-ethy1testosterone in 50 ml. methylene chloride and 25 ml. ethyl acetate was ozonized at 70 (acetone-Dry Ice bath) until the solution was blue in color. After oxygen was passed through, the solution was evaporated at room temperature in vacuo. The syrupy residue was then dissolved in 100 ml. of glacial acetic acid, and after addition of ml. of 30 percent hydrogen peroxide, left for 24 hours at 0-5. Following this time, it was evaporated to dryness, dissolved in 1500 ml. ether, and extracted with 2 N sodium carbonate solution. The alkaline extract was poured in ice cold hydrochloric acid. The resultant crystalline 17a-ethyl-17fl-hydroxy-5- oxo-3,S-seco-A-norandrostan-3-oic acid was filtered, washed with water and dried. Upon being recrystallized from acetone, it melted at 196-197".

Example 2 A solution of 1.5 g. of 17cx-ethyl-1718-hydroxy-5-oxo- 3,S-seco-A-norandrostan-3-oic acid in 100 ml. of methanol was titrated with 2 N sodium methoxide to the reddish color of phenolphthaleine, and then evaporated to dryness in vacuo, giving as the residue, the sodium salt of 17a-ethyl-l713-hydroxy 5 oxo 3,5-seco-A-norandrostan-3-oic acid. 5 g. of sodium-phenylacetate was add Example 2a To a solution of 100 mg. of 17a-etthy1-17B-hydroxy- IOB-desA-androstan-S-one in ml. of absolute ethanol was added one equivalent of sodium ethoxide dissolved in 5 ml. of absolute ethanol. This reaction mixture was maintained at room temperature overnight, then acidified with glacial acetic acid, poured in water and extracted with methylene chloride. The extract was washed with water, dried over anhydrous sodium sulfate and concen- 26 trated in vacuo. Thin layer chromatography showed the product to be Uni-ethyl-17,9-hydroxy-10a-desA-androstan- 5-one. It was obtained crystalline from petroleum etherether and melted at 89-95".

Example 3 1.13 g. of 17a-ethyl-17fl-hydroxy-IOa-deSA-androstan- 5-one was dissolved in 120 m1. of anhydrous ether (or 1.13 g. of 105-isomer was dissolved in 300 ml. of anhydrous ether), and after cooling in a salt-ice bath, several drops of 30 percent hydrobromic acid in acetic acid were added. This was followed by the dropwise addition during five minutes of 0.684 g. of bromine dissolved in 2 ml. of acetic acid. This addition was synchronized with the decoloration rate of the reaction mixture. Immediately after this, 5 ml. of a saturated solution of sodium bisulfite and 5 ml. of 2 N sodium carbonate solution were added. The mixture was then transferred into a separatory funnel, 500 ml. of ether added, shaken and separated. The ether part was washed with water, dried and evaporated. The resultant bromides were dissolved in 100 ml. of dimethylformamide, and after addition of 3 g. of lithium carbonate, the solution was heated at 100 for 45 minutes. After cooling, it was poured into one liter of ether, washed with water, 1 N hydrochloric acid, 2 N sodium carbonate, water, dried and evaporated. The residue was dissolved in 40 ml. of glacial acetic acid, 1.2 g. of sodium acetate and 1.2 g. of zinc powder added, and the so-formed mixture heated 10 minutes at It was then poured into one liter of ethylacetate and the resultant solution washed with saturated sodium bicarbonate, then with water, dried and evaporated. The residue was chromatographed on Florisil (adsorbent) column. The fraction with benzene and V2 percent ethylacetate in benzene gave regenerated starting material. Fractions with l and 2 percent ethylacetate in benzene gave l7a-ethyl- 175 hydroxy-desA-androst 9-en-5-one, which after sublimation (140 and 0.1 mm. Hg vacuum), was obtained as a glass. 36.6 (c.=1, CHCI Example 4 A suspension of 262 mg. of 5 percent rhodium on alumina catalyst in a mixture of 26 ml. of percent ethanol and 5.25 ml. of 2 N sodium hydroxide solution was pre-reduced (i.e. hydrogenated at room temperature and atmospheric pressure). To this was added a solution of 262 mg. of 17a-ethy1-17B-hydroxy-desA-androst-9-en- 5-one in 15 ml. of 95 percent ethanol, and the mixture then hydrogenated at atmospheric pressure and room temperature. After one mole-equivalent of hydrogen was absorbed, the reaction was stopped, the catalyst was separated by filtration, and the filtrate evaporated in vacuo. Glacial acetic acid (1 ml.) was added to the residue, which was then dissolved in 1 liter of ether. The cloudy solution which resulted was washed with 2N Na CO solution, then with water, dried and evaporated to dryness in vacuo.

The reaction was repeated 3 more times, and the combined products chromatographed on a Florisil (adsorbent) column. The eluates with 1 percent ethyl acetate in benzene gave first crystalline fractions, which were followed by non-crystalline fractions. The non-crystalline fractions were dissolved in ml. of methylene chloride, and after the addition of 2.5 ml. of 2 percent CrO in 90 percent acetic acid, stirred overnight. The excess of chromic acid was removed by washing the methylene chloride solution with 10 ml. of 10 percent sodium hydrogen sulfite solution, followed by washing with 2 N Na CO solution and then with water. It was then dried and evaporated in vacuo. The residue was dissolved in 50 ml. of anhydrous ethanol containing 172 mg. of sodium ethoxide, and left overnight. The next day, after addition of 0.5 ml. of glacial acetic acid, the solution was evaporated in vacuo, and the residue was taken up in 1 liter of ether. The ether solution was washed with 2 N Na CO solution, then with 27 water, dried and evaporated. The residue was chromatographed on Florisil (adsorbent) column and gave crystalline 17a-ethyl-l7/8-hydroxy-desA-9B,IOB-androstan-S-one identical (by thin layer chromatography) with the crystalline material obtained in the first chromatographic separation. After two recrystallizations from ether, it melted at 142144; [M -11.65 [methanol, c.=1.245 percent].

Example To a solution of 132 mg. of 17a-ethyl-17B-hydroxydesA-9B,lOfi-androstan-S-one in 12.5 ml. of absolute ethanol containing 34 mg. of sodium ethoxide, 0.15 ml. of freshly distilled methylvinyl ketone was added. The reaction mixture was then refluxed for two hours in a nitrogen atmosphere. After cooling the reaction mixture, 0.1 ml. of glacial acetic acid was added thereto and the resulting mixture was then poured into 1 liter of ether. The resultant ether solution was washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was chromatographed on fluorescent silica-gel plates, with the solvent system, 60 percent ethyl acetate-40 percent heptane. The fluorescent part of the layers was extracted with ethyl acetate. The residue obtained after evaporation of ethyl acetate was first crystallized from ether-petroleum ether, then a second time from pure ether, yielding 17a-ethy1-9 3,wot-testosterone, M.P. 131- 135.

Example 6 A solution of 6.4 g. of lla-hydroxy-progesterone in 100 ml. of ethylacetate and 50 ml. of methylene chloride was treated with ozone at 70 until the solution became blue in color. Oxygen was then passed through and the solution evaporated at room temperature in vacuo. The so-obtained syrupy residue was dissolved in 100 ml. of glacial acetic acid, and after the addition of 5 ml. of 30 percent hydrogen peroxide, left for 24 hours at 2 (in an ice box). The solution was then evaporated in vacuo, and the residue triturated with ether yielding crystals. Recrystallization from acetone yielded 1lu-hydroxy-3,5-seco- A-nor-pregnane-5,20-dione-3-oic acid 3,1l-1actone, M.P. 253-256. +193.3 (c.=1, in chloroform).

Example 7 A methanolic solution of 7.5 g. of 11a-hydroxy-3,5- seco-A-nor-pregnane-S,20-dione-3-oic acid 3,11-lactone was treated with one equivalent of 10 N sodium hydroxide solution and then evaporated to dryness. Sodium phenylacetate (26 g.) was added to the soobtained sodium salt and the mixture pyrolyzed at 295 for two hours in vacuo. The crude sublimate was chromatographed on a silica-gel column and eluted with 10 percent ethylacetate in benzene. The amorphous solid Ila-hydroxy 10m desA-pregnane-5,20-dione was first eluted from the column. IR-spectrum in chloroform: 3620 and 3600 cm:- (-OH); 1706 cm. (carbonyl group). NMR- spectrum in deuterochloroform: a doublet for loot-CH at 73.5 and 80.5 c.p.s., downfield from TMS at 60 mc./sec. Further elution of the column with 10 percent ethylacetate in benzene yielded crystalline 11oz hydroxy-lOfi-desA- pregnane-5,20-dione which was recrystallized from methylene chloride-petroleum ether, M.P. 150-152; [M +84.0 (c. =0.5 in absolute ethanol).

Example 8 To a solution of 100 mg. of methanesulfonylchloride in 0.7 ml. of pyridine, there was added 100 mg. of 11ahydroxy-10/3-desA-pregnane-S,20-dione. The mixture was then allowed to stand overnight at 2 (in a refrigerator), then was diluted with water (100 m1.) and extracted with chloroform (3X 150 m1.) and methylene chloride (100 ml.). The combined organic extracts were washed with water, 1 N hydrochloric acid and again with water, then dried over anhydrous sodium sulfate and evaporated in 28 vacuo. The crystalline residue was recrystallized from ether, giving hydroxy-10fi-desA-pregnane-S,20-dione methanesulfonate, M.P. 139-140"; [0:] +46 (c.=0.5 in absolute ethanol).

Example 9 A solution of 200 mg. of lla-hydroxy-lOfi-desA- pregnane-5,20-dione methanesulfonate in 50 ml. of dimethylformamide was refluxed for eight hours and then evaporated to dryness. The residue was chromatographed on a Florisil (adsorbent) column. Elution with 2 percent ethylacetate/benzene and evaporation of the eluant yielded desA-pregn-9-ene-5,20-dione in the form of colorless needles, M.P. Ill-113. It was shown 'by mixed melting point to be identical with a sample of the same compound prepared as described in Example 12.

Example 10 To a solution of 20 g. of lla-hydroxy-progesterone in 150 ml. of pyridine maintained at 0, there was added 6 ml. of methanesulfonylchloride, and the reaction mixture allowed to stand overnight at 0. It was then diluted with a large excess of water and extracted with chloroform. The organic extracts were washed with 2 N hydrochloric acid and water, then dried over anhydrous sodium sulfate and evaporated in vacuo. The solid residue was recrystallized from methanol to give llwmesyloxyprogesterone, M.P. 159.S1'60; [ad l45.6 (c.=l, chloroform).

Example 11 A solution of 12 g. of 1la-mesyloxy-progesterone in 300 ml. of methylene chloride/ethyl acetate (2:1) was treated with ozone at 70 until the solution became blue in color. The excess of ozone was removed by bubbling oxygen through the reaction mixture for five minutes. Methylene chloride was then removed under reduced pressure, and the solution diluted with ethyl acetate to 200 ml. After addition of 12 ml. of 30 percent aqueous hydrogen peroxide, the reaction mixture was then allowed to stand overnight at 2 (i.e., in the refrigerator), then evaporated to a volume of 75 ml. and diluted with ml. of benzene. The aqueous solution, obtained by extraction with 8 portions of 75 ml. 2 N sodium carbonate followed by combining the aqueous extracts was acidified with cold concentrated hydrochloric acid to pH 2 and extracted with methylene chloride. This extract was dried over anhydrous sodium sulfate and evaporated in vacuo to dryness. The residue crystallized when triturated with ether-acetone mixture, yielding crude 11amesoxy-5,20-dioxo-3,S-seco A nor-pregnan-3-oic acid. After recrystallization from acetone-petroleum ether, M.P. 152153; [M 47.9 (c.=1, chloroform).

Example 12 A solution of 6 g. of 11a-mesoxy-5,20-dioxo-3,S-seco-A- nor-pregnan-3-oic acid in ml. of methanol was mixed with a solution of 1.5 g. of sodium carbonate in 55 ml. of water. The mixture was then transferred into a 1 liter sublimation flask, and evaporated to dryness. To the thus formed sodium salt, 20 g. of sodium phenyl acetate is added, and after closing the top part of the apparatus, this mixture was pyrolyzed at 290 and 0.02 mm. for four hours. The product, which collects on the cold finger, was dissolved in ether and filtered. The filtrate was then evaporated to dryness. Purification of the residue by chromatography on a 40 g. silica-gel column (benzene eluant) gave crystalline desA-pregn 9 ene-5,20-dione; M.P. Ill-113 (after recrystallization from ether). [ah-f l+56.8 (c.=0.25 percent in methanol).

Example 13 To a solution of 1.2 g. of desA-9-ene-5,20-dione in 20 ml. of methanol maintained at 0, there was slowly added a cooled solution of 1.2 g. of sodium borohydride in 22 ml. methanol, and the resultant mixture was left for 72 hours at 'It was then diluted with 100 ml. of water and extracted with four 100 ml. portions of chloroform. The extract was dried over anhydrous sodium sulfate and evaporated in vacuo, yielding a colorless oily product. This product was dissolved in 250 ml. of chloroform and 6 g. of manganese dioxide was added to the solution which was then stirred for 72 hours at room temperature, filtered and the filtrate evaporated to dryness in vacuo. The residue was chromatographed on a silicagel column and the eluates with percent ethyl acetate in benzene, after concentration gave crystalline 20pxhydroxy-desA-pregn-9-en-5-one which upon recrystallization from methylene chloride-petroleum ether formed colorless needles, M.P. 122123; 33 (c.=0.5, absolute ethanol).

Example 14 A suspension of 262 mg. of 5 percent rhodium on alumina catalyst in a mixture of 26 ml. of 95 percent ethanol and 5.25 ml. of 2 N aqueous sodium hydroxide was hydrogenated at room temperature and atmospheric pressure. To this was added a solution of 262 mg. of 20B-hydroxy-desA-pregn-9-en-5-one in 15 ml. of 95 percent ethanol, and the reaction mixture then hydrogenated at room temperature and atmospheric pressure. After one mole equivalent of hydrogen was absorbed, the reaction was stopped, and the catalyst was separated by filtration. After standing overnight the filtrate was concentrated in vacuo. To the residue was added 1 ml. of glacial acetic acid, and it was then dissolved in 1 liter of ether. The cloudy solution was washed with 2 N aqueous sodium carbonate solution, then with water, then dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. It yielded a colorless oil, which was chromatographed on a silica-gel column using 1 percent ethyl acetate in benzene as the elutant. First eluted was 20,8-hydroxy-u-desA pregnan 5 one, M.P. 107-108 after recrystallization from methylene chloride/ petroleum ether. R.D. (in methanol); 25.3, [@1 89'; 1350 1305 1300 Further elution yielded 20/3 hydroxy 95,1013 desA- pregnan-S-one as a colorless oil. R.D. (in methanol): 1500 [M1400 1350 H' 1310 +2148.

Example A suspension of 262 mg. of 5 percent rhodium on alumina catalyst in a mixture of 2 ml. of 3 N aqueous hydrochloric acid and 18 ml. 95 percent ethanol was hydrogenated at room temperature and atmospheric pressure. A solution of 262 mg. of ZOB-hydroxy-desA- pregn-9-en-5-one in 5 ml. of absolute ethanol was introduced into the hydrogenation flask, and the reaction mixture was then hydrogenated at room temperature and atmospheric pressure. After one mole-equivalent of hydrogen was absorbed, the reaction was stopped, the catalyst was separated by filtration, and the filtrate neutralized with 2 N aqueous sodium hydroxide solution. An excess of 5 ml. of 2 N aqueous sodium hydroxide was added and the solution allowed to stand overnight. Ethanol was then removed by evaporation at reduced pressure, and after addition of 1 ml. of glacial acetic acid, it was extracted with 1 liter of ether. The extract was washed with 2 N aqueous sodium carbonate solution, then with water, dried and concentrated in vacuo. It gave a colorless oil, which was chromatographed on a silica-gel column using 2 percent ethyl acetate in benzene as the elutant. The first fractions of the eluate yielded, upon concentration, 20,3- hydroxy-10a-desA-pregnan-5-one. From the immediately subsequent fraction, 8 hydroxy-9B,IOB-desA-pregnan-S- one was obtained. Both products were identical with the same compounds obtained in Example 14.

30 Example 16 20fl-hydroxy-9fi,l0a-pregn-4-en-3 one is prepared by condensation of 20,3-hydroxy-9B,IOB-desA-pregnan-S-one with methyl vinyl ketone according to the procedure of Example 5. The product melts at l76.5-l78.5; [M -l43 (chloroform).

Example 17 A medium is prepared of 20 g. of Edamine enzymatic dgest of lactalbumin, 3 g. of corn steep liquor and 50 g. of techanical dextrose diluted to 1 liter with tap water and adjusted to a pH of 4.3-4.5. Twelve liters of this sterilized medium is inoculated with Rhizopus nigricans minus strain (A.T.C.C. 6227b) and incubated for 24 hours at 28 using a rate of aeration and stirring such that the oxygen uptake is 6.3-7 millimoles per hour per liter of Na SO according to the method of Cooper et al., Ind. Eng. Chem., 36, 504 (1944). To this medium containing a 24 hour growth of Rhizopus nigricans minus strain, 6 g. of l7a-acetoxy-progesterone in ml. of acetone is added. The resultant suspension of the steroid in the cultrue is incubated under the same conditions of temperature and aeration for an additional 24 hour period after which the beer and mycelium are extracted. The mycelium is then filtered, washed twice, each time with a volume of acetone approximately equal in volume to the mycelium, extracted twice, each time with a volume of methylene chloride approximately equal to the volume of the mycelium. The acetone and methylene chloride extracts including solvent are then added to the beer filtrate. The mixed extracts and beer filtrate are then extracted successively with 2 portions of methylene chloride, each portion being /2 the volume of the mixed extracts and beer filtrate, and then with 2 portions of methylene chloride, each portions being A the volume of the mixed extracts and beer filtrate. The combined methylene chloride extracts are then washed with 2 portions of a 2 percent aqueous solution of sodium bicarbonate, each portion being the volume of the combined methylene chloride extracts. The methylene chloride extracts are then dried with about 35 g. of anhydrous sodium sulfate per liter of solvent, and then filtered. The solvent is then removed from the filtrate by distillation, and the residue is dissolved in a minimum of methylene chloride, filtered and the solvent evaporated from the filtrate. The resulting crystals are then dried and washed five times, each time with a 5 ml. portion of ether per gram of crystal. The crystals are then recrystallized from ether giving 17aacetoxy-l la-hydroxy-progesterone. 17ot-acetoxy-l lot-mesoxy-progesterone is prepared by treatment of 17u-acetoxy 11oz hydroxy progesterone with methanesulfonyl chloride, according to the procedure of Example 10.

Example 18 17a-acetoxy-5,20-dioxo-llot-mesoxy-A-nor 3,5 secopregnan-S-oic acid is prepared by ozonolysis of 17aacetoxy-llot-mesoxy-progesterone, according to the procedure of Example 11.

Example 19 l7a-acetoxy-desA-pregn-9-ene-5,20-dione is prepared from l7u-acetoxy-5,20-dioxo-l la-mesoxy-A-nor-3,S-secopregnan-3-oic acid by conversion of the latter to its sodium salt followed by pyrolysis, according to the procedure of Example 12.

Example 20 17m-acetoxy-20fl-hydroxy-desA-pregn-9-en-5-one is prepared from 17a-acetoxy-desA-pregn-9-en-5,20 dione by reduction and reoxidation according to the procedure of Example 13.

Example 21 l7a-acetoxy-20fl-hydroxy-9j3,IO B-desA-pregnan-S-One is prepared from l7a-acetoxy-20fl-hydroxy-desA-pregn-9-en- 5-one by hydrogenation under acidic conditions in the presence of a rhodium catalyst, according to the procedure of Example 15.

Example 22 17a-acetoxy-20B-hydroxy-9B,lOa-pregn-4-en-3 one is prepared by condensing methyl vinyl ketone with 17a.- acetoxy-2QB-hydroxy-9 8,10fi-desA-pregnan-5-one accord ing to the procedure of Example 5 except instead of conducting the condensation in absolute ethanol and catalyzing it with sodium ethoxide, the condensaiton is conducted in acetic acid and is catalyzed with p-toluene sulfonic acid.

Example 23 20fl-hydroxy-4-methyl-9B,l0a-pregn-4-en-3-one is prepared by condensing 20B-hydroxy-9fi,IOB-desA-pregnan-S- one and ethyl vinyl ketone according to the procedure of Example 5.

Example 24 17/3-hydroxy-5-oxo-3,5-seco-A-nor-androstan-3-oic acid is prepared by ozonolysis of testosterone according to the procedure of Example 1.

Example 25 17/9-hydroxy-loa-desA-androstan 5 one and 17,8-hydroxy-lp-desA-androstan-5-one are prepared from 17/3- hydroxy--oxo-3,5-seco-A-norandrostan-3-oic acid by conversion of the latter to its sodium salt followed by pyrolysis, according to the procedure of Example 2.

Example 26 17fl-hydroxy-desA-androst-9-en-5-one is prepared from l7i3-hydroxy-10a-desA-androstan-S-one by bromination followed by dehydrobromination, according to the procedure of Example 3.

Example 26a DesA-androst-9-ene-5,17-dione is prepared from 175- hydroxy-desA-androst-9-en-5-one by oxidation of the latter with 2 percent chromic acid solution in 90 percent acetic acid. The so-obtained desA-androst-9-ene-5,l7-dione is recrystallized from cyclohexane and melts at 123- 123.5";

l li +83 (c.=0.l021, dioxane).

Example 27 A solution of 236 mg. of 17B-hydroxy-desA-androst-9- en-S-one in 40 ml. 95 percent ethanol and 5.25 ml. 2 N aqueous sodium hydroxide solution was hydrogenated with one mole equivalent of hydrogen over 236 mg. of prereduced 5 percent rhodium on alumina catalyst. After separation of catalyst, the solution was concentrated in vacuo to dryness, and the residue taken up in one liter of ether. The ether soluiton was Washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. From the residue l7fi-hydroxy-9/3,10fl-desA- andrQstan-S-one was obtained by crystallization. M.P. 144.5-145; 22 (c.=0.103; dioxane). The 17,3- acetate (i.e. l7B-acetoxy-9 3,IOB-desA-androstan-S-one) is obtained by acetylation of testosterone followed by ozonolysis, pyrolysis, bromination and dehydrobromination, and reduction according to the methods of Examples 24, 25, 26 and 27 respectively, and melts at 118119; [111 9 28 (c.=0.103; dioxane).

Example 28 A solution of 238 mg. of 17fi-hydroxy-9/3,10fl-desA- androstan-S-one, 1 ml. of ethylene glycol and catalytic amount of p-toluene sulfonic acid in 100 ml. of anhydrous benzene was slowly distilled until no more water was coming over. The solution was then concentrated in vacuo to a small volume, and 17 3-hydroxy-9fi,10p-desA- 32 androstan-S-one S-ethylene ketal was obtained from the residue by crystallization. M.P. -116"; [a];, 9 (c.=0.0987; dioxane).

Example 29 To a solution of 282 mg. of 17/3-hydroxy-9fi,10;9-desA- androstan-S-one S-ethylene ketal in 50 ml. of methylene chloride was added 1 equivalent of 2 percent chromic acid in pyridine, and the reaction mixture then stirred overnight. The reaction mixture was then washed with 10 percent aqueous sodium hydrogen sulfite, 2 N aqueous sodium carbonate, Water, then dried over anhydrous sodium sulfate and concentrated in vacuo to dryness. Crystallization of the residue gave 95,105 desA-androstane-5,17- dione S-monoethylene ketal. Splitting of the ketal in acetone solution in the presence of a catalytic amount of ptoluene sulfonic acid gives 9,8,10,6,des-A-androstane-5,17- dione which melts, after recrystallization from cyclohexane, at 77.578; [0:]; +55 (c.=0.107; dioxane).

Example 30 To a preformed solution of one mole equivalent of prop-1'-inyl lithium in 100 ml. of anhydrous liquid ammonia was added tetrahydrofuran solution of 200 mg. of 9,8,105 desA-androstane-S,17-dione S-mono-ethylene ketal, and the reaction mixture stirred for two hours. After addition of one gram of ammonium chloride, cooling was discontinued, and the reaction mixture allowed to evaporate. The residue was extracted with methylene chloride, the extract was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in 20 ml. of acetone and the catalytic amount of p-toluenesulfonic acid added, and the solution was refluxed for two hours, then poured in water and extracted in methylene chloride. The methylene chlorine extract was washed with water, then dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. Crystallization of the residue gave a (prop-1'-inyl)-17B-hydroxy-9,3,10;3-desA- androstan-S-one.

Example 31 17oz (prop 1'-inyl)-17;3-hydroxy-9;3,10a-androstan-4- en-3-one is prepared by condensing methyl vinyl ketone with 17a (prop 1-inyl)-17p-hydroxy-9p,IOB-desA-androstan-S-one according to the procedure of Example 5. The product melts at 164-165 Example 32 To a stirred solution of one mole equivalent of 2-methyl-prop-2-enyl magnesium bromide in 100 ml. of ether at room temperature was added dropwise a solution of 280 mg. of 9 8,IOB-desA-androstane-S,17-dione 5-mono-ethylene ketal in 100 ml. of tetrahydrofuran. The reaction mixture was refluxed for one hour. After cooling in an icesalt bath, a saturated solution of sodium sulfate was slowly added to decompose the Grignard complex. This was followed by addition of anhydrous sodiumsulfate. The solution was separated by filtration and concentrated in vacuo to dryness. The solution of the residue and of a catalytic amount of p-toluene sulfonic acid in 20 ml. of acetone was refluxed for two hours, then poured in water and extracted in methylene chloride. Methylene chloride extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. From the residue 170; (2'-methyl-prop-2'-enyl)-17/3-hydroxy-9,B,IOB-desA- androstan-S-one was obtained.

Example 33 17a (2'-methyl-prop-2'-enyl)-17,B-hydroxy-9;8,IDOL-androst-4-en-3-one is prepared from 17a-(2'-methyl-prop-2'- enyl)-17/3-hydroxy-9p,IOB-desA-androstan-S-one by condensation of the latter with methyl vinyl ketone according tche procedure of Example 5. The product melts at 106- 1 33 Example 34 16c: acetoxy-20-ethylenedioxy-pregn-4-en-3-one is prepared by acetylation of 16a hydroxy-ZO-ethylenedioxypregn-4-ene-3,20-dione with one equivalent of acetic anhydride in pyridine solution at room temperature for 2 hours, followed by concentration to dryness in vacuo. 16aacetoxy 20-ethylenedioxy-5-oxo-3,5-seco-A-norpregnan- 3-oic acid is prepared by ozonolysis of l6a-acetoxy-20- ethylenedioxy-pregn-4en-3-one according to the procedure of Example 1.

Example 35 16c: acetoxy-2O-ethylenedioxy-IOu-deSA-pregnan-S-One and 16a acetoxy-20-ethylenedioxy-lOfi-desA-pregnan-S- one are prepared from 16oz acetoxy-20-ethylenedioxy-5- oXo-3,S-seco-A-norpregnan-3-oic acid by conversion of the latter to its sodium salt followed by pyrolysis (according to the procedure of Example 2) and reacetylation with acetic anhydride and pyridine.

Example 36 16oz acetoxy-20-ethylenedioxy-desA-pregn-9-en-50ne is prepared from 16a-acetoxy-20-ethylenedioxy-IOa-desA- pregnan one by bromination followed by dehydrobromination, according to the procedure of Example 3.

Example 37 16a acetoxy-20-ethylenedioxy-9/8,10p-desA-pregnan-5- one is prepared from l6u-acetoxy-20-ethylenedioxy-desA- pregn-9-en-5-one by hydrogenation under basic conditions in the presence of a rhodium catalyst, according to the procedure of Example 14.

Example 38 16oz hydroxy 20-ethylenedioxy-9fi,l0a-pregn-4-en-3- one is prepared by condensing l6u-acetoxy-20-ethylenedioxy-desA-9B,lOfl-pregnan-S-one with methyl vinyl ketone according to the procedure of Example 5.

Example 39 160: methyl-ZO-ethylenedioxy-IOu-desA-pregnan-S-One and 16a-methyl-20-ethylenedioxy-IOB-desA-pregnan-S-one are prepared from 16a-methyl-20-ethylenedioxy-S-oxo-3, 5-seco-A-norpregnan-3-oic acid by conversion of the latter to its sodium salt followed by pyrolysis, according to the procedure of Example 2.

Example 41 16a methyl-ZO-ethylenedioxy-desA-pregn-9-en-5-one is prepared from 16a methyI-ZO-ethylenedioxy-lOat-desA- pregnan-S-one by bromination followed by dehydrobromination, according to the procedure of Example 3.

Example 42 l6a-methyl-ZO-ethylenedioxy 95,1013 desA pregnan- S-one is prepared from 160: methyl 20 ethylenedioxydesA-pregn-9-en-5-one by hydrogenation under basic conditions in the presence of a rhodium catalyst, according to the procedure of Example 14.

Example 43 l6a-methyI-ZO-ethylenedioxy 95,100; pregn 4 en- 3-one is prepared by condensing 16a-methyl-20-ethylenedioxy-9B,IOB-desA-pregnan-S-one with methyl vinyl ketone, according to the procedure of Example 5.

Example 44 2l-acetoxy-'1la-hydroxy 20 ethylenedioxy pregn-4- en-3-one is prepared by microbiological treatment of 21- acetoxy-ZO-ethylene-dioxy-pregn-4-en-3-one, according to the procedure of Example 17. 2l-acetoxy-1la-mesoxy-20- ethylenedioxy-pregn-4-en-3-one is prepared by treatment of 2l-acetoxy 11a hydroxy 20 ethylenedioxy-pregn- 4-ene-3-one with methanesulfonyl chloride, according to the procedure of Example 10.

Example 45 21-3C6tOXY-11a-H1CSOXY 20 ethylenedioxy-5-oxo-3,5- seco-A-norpregnan-3-oic acid is prepared by ozonolysis of 2l-acetoxy-llu-mesoxy-20-ethylenedioxy pregn 4 en- 3-one, according to the procedure of Example 11.

Example 46 21-acetoxy-20-ethylenedioxy desA pregn 9 en-S- one is prepared from 2l-acetoxy 20= ethylenedioxy-llumesoxy-3,5-seco-A-norpregnan-3-oic acid by conversion of the latter to its sodium salt followed by pyrolysis, according to the procedure of Example 12, except that the crude product is reacetylated by treatment with acetic anhydride/ pyridine prior to its being worked-up.

Example 47 2l-acetoxy 20 ethylenedioxy 9fl,l05 desA-pregnan-S-one is prepared from 21-acetoxy-ZO-ethylenedioxydesA-pregn-9-en-5-one by hydrogenation under acidic conditions in the presence of a rhodium catalyst, according to the procedure of Example 15.

, Example 48 2l-hydroxy-20-ethylenedioxy 9,6,101: pregn-4-en-3- one is prepared from 2l-acetoxy-20-ethylenedioxy-9fi,10B- desA-pregnan-S-one by condensing the latter with methyl vinyl ketone, according to the procedure of Example 22.

Example 49 lla-rnesoxy 16a,17a isopropylidenedioxy-progesterone is prepared by treatment of lla-hydroxy-l6a,l7a-isopropylidenedioxy progesterone with methane sulfonyl chloride, according to the procedure of Example 10.

Example 50 5,20 dioxo-l1u-mesoxy-16a,17a-isopropylidenedioxy- 3,5-seco-A-norpregnan-3-oic acid is prepared by ozonolysis of 1la-mesoxy-l6u,l7a-isopropylidenedioxy-progesterone, according to the procedure of Example 11.

Example 51 l6a,17u-isopropylidenedioxy desA pregn-9-en-5,20- dione is prepared from 5,20-dioxo11a-mesoxy-16a,17aisopropylidenedioxy-3,5-seco-A-norpregnan-3-oic acid by conversion of the latter to its sodium salt, followed by pyrolysis according to the procedure of Example 12.

Example 52 20/3 hydroxy 16:1,170: isopropylidenedioxy desA- pregn-9-en-5-one is prepared from 16a,l7a-isopropylidenedioxy-desA-pregn-9-ene-5,20-dione by reduction and reoxidation, according to the procedure of Example 13.

Example 53 20B hydroxy 160:,170: isopropylidenedioxy-JOB- desA-pregnan 5 one is prepared from 20 3-hydroxy- 16,l7a isopropylidenedioxy-desA-pregn-9-en-5-one by hydrogenation according to the procedure of Example 14.

Example 54 20,3 hydroxy l6a,17oc isopropylidenedioxy-9 3,10apregn-4-en-3-one is prepared by condensing methyl vinyl ketone with 20,8-hydroxy 16a,17a-isopropylidenedioxydesA-9,8,10fl-pregnan--one according to the procedure of Example 5.

Example 55 700,17oc dimethyl 17,8 hydroxy 5 oxo-3,5-seco-A- norandrostan-3-oic acid is prepared from 7a,17a-dimethyltestosterone by ozonolysis of the latter, according to the procedure of Example 1.

Example 56 Example 57 7u,17u-dimethyl 17B hydroxy desA androst-9-en- 5-one is prepared from 7a,17oc-dimthyl- 17;9-hydroxy- 10a-desA-androstan-5-one by bromination followed by dehydrobromination, according to the procedure of Example 3.

Example 58 7a,17u-dimethyl 17 3 hydroxy desA-9B,10,B-androstan-S-one is prepared from 7a,17a-dimethyl 175 hydroxy-desA-androst-9-en-5-one by hydrogenation in the presence of a rhodium catalyst, according to the procedure of Example 4.

Example 59 7,17a-dimethyl 9,6310 testosterone is prepared from 7a,17a-dimethyl 17p hydroxy-desA-9B,IOfi-androstan- 5-one by condensing the latter with methyl vinyl ketone, according to the procedure of Example 5.

Example 60 =1la-mesoxy-17a-methyl-progesterone is prepared from 1lu-hydroxy-l7a-methyl-progesterone by treatment of the latter with methane sulfonyl chloride, according to the procedure of Example 10.

Example 61 lla-mesoxy 17a methyl 5,20 dioxo 3,5 seco-A- norpregnan-3-oic acid is prepared from 11oz-1Il6SOXy-17ozmethyl-progesterone by ozonolysis of the latter, according to the procedure of Example 11.

Example 62 17u-methyl-desA-pregn-9-ene 5,20 dione is prepared from lla-mesoxy 17cc methyl 5,20 dioxo-3,5-secoA- norpregnan-3-oic acid by conversion of the latter to its sodium salt followed by pyrolysis, according to the procedure of Example 12.

Example 63 20,8-hydroxy-17u-methyl-desA-pregn-9-en-5-one is prepared from 17a-methyl-desA-pregn 9 en 5,20 dione according to the procedure of Example 13.

Example 64 20,8 hydroxy 17oz methyl 913,105 desA-pregnan- 5-one is prepared from 170; methyl-ZOfi-hydroxy-desA- pregnan-9-ene-5-one according to the procedure of Example 15.

Example 65 20,8 hydroxy 17a methyl 9 8,l0a-pregn-4-en-3-one is prepared by condensing 17ot-methyl-20j8-hydroxy-9 3, IOfl-desA-pregnan-S-one with methyl vinyl ketone, according to the procedure of Example 4.

Example 66 A solution of 12.8 g. of 17u-methyltestosterone in 200 ml. of methylene chloride and 100 ml. of ethyl ace- 36 tate was ozonized for 1 hour and 5 minutes at -70 (acetone-Dry Ice bath) until a blue color developed. After oxygen was bubbled through, the solution was then concentrated at room temperature in vacuo. The residue was dissolved in 400 ml. of acetic acid, and after addition of 30 ml. of 30% hydrogen peroxide, the solution was left overnight at 0. It was then evaporated to dryness in vacuo, the residue taken up in ether, and the ether solution extracted with 2 N aqueous sodium carbonate (12X 50 ml.). The combined carbonate extracts were cooled in ice, and acidified with concentrated hydrochloric acid. The aqueous suspension of precipitated organic acid was extracted with methylene chloride, this extract was washed with water, dried over anhydrous sodium sulfate and evaporated giving as a colorless crystalline material hydroxy 17a methyl 5 oxo 3,5 seco A norandrostan-3-oic acid. After recrystallization from acetonehexane, it melted at -197, [a] =9.8 (c.=1.0 in chloroform) Example 67 A solution of 10 g. of l7fi-hydroxy-17a-methyl-5-oxo- 3,5-seco-A-nor-androstan-3-oic acid in 250 ml. of methanol was made alkaline to phenolphthalein with sodium ethoxide, and evaporated to dryness. The residual powdery sodium salt was mixed well with 32 g. of sodium phenylacetate and 40 g. of neutral alumina (Woelm, Grade I), and the mixture heated at 290 in vacuo for 4 hours. After cooling to room temperature, a large excess of water was added, and the resultant suspension extracted with 2 liters of ether. The ether extract was washed with water, aqueous 2 N sodium carbonate solution, and again with water, dried and evaporated. This gave a sirupy residue, which by thin layer chromatograms and infrared spectra consisted of 17/3-hydroxy-17a-methyl-10a-desA androstan-S-one as the major and l7fi-hydroxy-l7amethyl-lOp-desA-androstan-S-one as the minor product.

Three additional pyrolyses were performed as described above, and the combined products so-obtained was chromatographed on a 850 g. silica gel column, using 5% ethylacetate in benzene as the eluent. This chromatography yielded 17,8 hydroxy 17a methyl-10m-desA- androstan-S-one, which after recrystallization from petroleum ether melted at 9697, [or] -=28.2 (c.0.5 in chloroform).

Further eluates of the column gave product, 17B-hydroxy -17a methyl 10B desA-androstan-S-one which, when recrystallized from ether, melted at 165167, [u] =19.8 (c.=0.5 in chloroform).

To a solution of 2.2 g. of the mixture of 17,8-hydroxy- 17a methyl 10cc desA-androstan-S-one and 17,8-hydroxy-17ot-mthyl-lOB-desA-androstan-S-one (obtained by the above pyrolysis procedure) in 50 ml. of absolute ethanol were added 20.1 ml. of a solution prepared by dissolving 2.48 g. of sodium metal in 250 ml. of absolute ethanol. The reaction mixture was stirred overnight at room temperature. It was then acidified with 2 ml. of glacial acetic acid, and evaporated to dryness. The residue was extracted in ether (1 liter) and the ether extract washed with water, dried, and evaporated. The residue was crystallized from petroleum ether giving a quantitative yield of 17p hydroxy 17cc methyl 10cc desA-androstan- 5-one.

Example 68 To a solution of 11.2 g. of 17,8-hydroxy-17u-methyll0a-desA-androstan-5-one in -1260 ml. of anhydrous ether, stirred and cooled in an ice-salt bath, were added first several drops of 30% hydrogen bromide in acetic acid, then dropwise a solution of 7.16 g. of bromine in 20 ml. of glacial acetic acid. The rate of addition of the bromine solution was synchronized with the rate of disappearance of excess bromine. After bromination was complete, 53 ml. of 10% sodium hydrogen sulfite Solution and 53 ml.

37 of aqueous 2 N sodium carbonate solution were added to the reaction mixture while stirring. The ether layer was then separated, washed with water, dried, and evaporated to dryness in vacuo. The residue was dissolved in 250 ml. of dimethylformamide, and heated with 7.5 g. of lithium carbonate at 100 for 45 minutes. After cooling, 2 liters of ether were added and the ether solution washed with water, 1 N hydrochloric acid, and then again with water, dried and evaporated. The residue was dissolved in 200 ml. of glacial acetic acid, 12.6 g. of sodium acetate and 12.6 g. of zinc powder were added and the mixture heated for ten minutes at 80. After cooling to room temperature, the reaction mixture was filtered, and evaporated. The residue was dissolved in ethylacetate, and washed with saturated sodium bicarbonate solution, then with Water, dried and evaporated. The so-obtained residue was chromatographed on a silica gel column using 10% ethylacetate in benzene as the eluent which gave first 17B- hydroxy 17oz methyl 10a desA androstan -one, followed by 17B-hydroxy-17a-methyl-desA-androst-Q-en- 5-one. After recrystallization from ether, the latter compound melted at 103104, [a] =63.2 (c.=0.5 in chloroform).

Example 69 A suspension of 1.25 g. of 5% rhodium on alumina catalyst in a mixture of 130 ml. of 95% ethanol and 26 ml. of 2 N sodium hydroxide was prereduced. To this was then added a solution of 1.25 g. of 17 3-hydroxy-17amethyl-desA-androst-9-en-5-one in 75 m1. of 95% ethanol, and then the mixture was hydrogenated at atmospheric pressure and room temperature. After one mole equivalent of hydrogen was absorbed, the reaction was stopped, the catalyst was moved by filtration, and the filtrate evaporated in vacuo. To the residue 5 ml. of glacial acetic acid was added, the so-formed mixture then dissolved in 2 liters of ether, and the resultant cloudy solution was washed with water, then dried and evaporated. The residue was dissolved in 50 ml. of methylene chloride and oxidized with 5 ml. of 2% chromic acid in 90% acetic acid until green color of reaction mixture. After then being washed with sodium hydrogen sulfite solution 2 N sodium carbonate solution and water, the reaction mixture was dried over sodium sulfate and evaporated. The residue was chromatographed very slowly on a 50 g. silica gel column, with 5% ethylacetate in benzene, and followed with thin layer chromatography. First, 17,6- hydroxy 17a-methyl-9a,l0a-desA- androstan-S-one was eluted. After a minor amount of mixed material, 17B-hydroxy-17a-methyl-9,8,10,6-desA- androstan-S-one was eluted. After recrystallization from ether-petroleum ether, it melted at 94-96".

Example 70 17a-methyl 95,100 testosterone is prepared from 17a-methyl 17B hydroxy-desA-9fl,1OB-androstan-S-one by condensation of the latter with methyl vinyl ketone, according to the procedure of Example 5. The product melts at 128-129".

Example 71 A solution of 6 g. of 11a,ZOfl-diacetoxy-pregn-4-en-3- one in 100 ml. methylene chloride and 50 ml. of ethylacetate was ozonized at 70. After methylene chloride was removed by distillation in vacuo, the residual solution was diluted to 100 ml. with ethylacetate. To this 5 ml. of 30 percent hydrogen peroxide was added and left overnight at room temperature. The reaction mixture was concentrated to dryness in vacuo, the residue taken up in 1 liter of ether, and the resulting solution extracted 10 times with 50 m1. portions of 2 N aqueous sodium carbonate. The carbonate extract was then acidified with ice-cold concentrated hydrochloric acid. The precipitated product was separated by filtration, and crystallized to give 11oz,20{5 diacetoxy 5 oxo 3,5 seco-A-nor-pregnan- 3-oic acid.

38 Example 72 A methanolic solution of 5 g. of 110:,20B-di2iC6tOXY- 5-oxo 3,5 seco-A-nor-pregnan 3 oic acid was treated with one-half mole equivalent of sodium carbonate, and evaporated to dryness in vacuo. Potassium acetate (5 g.) was added to the residue which was then pyrolyzed at 295 and 0.02 mm. The sublimate was chromatographed on a silica-gel column to give 11u,20B-diacetoxy-10B- desApregnan-5-one.

Example 73 Bromination and dehydrobromination starting with 11a,20/3-diacetoxy 10,6 desA-pregnan 5 one accord ing to the procedure of Example 3, gave 1la,20fi-diacetoxy-desA-pregn-9-en-5-onc.

Example 74 Hydrogenation of 110:,205 diacetoxy desA pregn- 9-en-5-one in ethanolic hydrochloric acid over 5 percent rhodium on alumina catalyst at room temperature and atmospheric pressure according to the procedure of Example 15 gave 1la,20fl-diacetoxy-9/8,IOfi-desA-pregnan- 5-one.

Example 75 1104,2013 diacetoxy 913,105 desA-pregnan 5 one was hydrolyzed in methanol solution with one mole equivalent of potassium carbonate to give 1la,2013-dihydroxy-9 3,10/8-desA-pregnan-5-one.

Example 76 Condensation of 110;,206 dihydroxy 918,10/3 desA pregnan-S-one with methyl vinyl ketone according to the procedure of Example 5 gave 1111,205 dihydroxy- 95,10a-pregn-4-en-3-one.

Example 77 A solution of 3 g. of 17a ethyl 17,3 hydroxyandrosta 1,4 dien 3 one in 75 ml. of methylene chloride and 25 ml. of ethyl acetate was ozonized at 70 till it became blue. After evaporation to dryness, the residue was dissolved in ml. of glacial acetic acid containing 5 ml. of 30 percent hydrogen peroxide, and set at room temperature for 2 days. The reaction mixture was concentrated to dryness and the residue dissolved in one liter of ether. The ether solution was then extracted 10 times with 25 ml. portions of aqueous 2 N sodium carbonate solution, and the carbonate extracts were acidified with ice-cold concentrated hydrochloric acid. The non-crystalline precipitate containing 17:!- ethyl 1718 hydroxy 10oz carboxy desA androstan- 5-one was separated by filtration and dried, then dissolved in 135 ml. of absolute ethanol, and after addition of 9 ml. of aqueous 2 N sodium hydroxide, boiled for 1 hr. The reaction mixture was concentrated in vacuo to a small volume, and diluted with 1750 ml. of ether. The ether solution was washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to dryness. The residue was crystallized from ether-petroleum ether, to give 17a ethyl 17B hydroxy 10oz desA- androstan-S-one, M.P. 89-90.

Example 78 3-(175-hydroxy 5 oxo 3,5 seco-A-nor-androstan- 17a yl 3 oic acid)-propionic acid lactone is prepared by ozonolysis of 3-(3-0xo 17,9 hydroxy-androst-4-en- 17u-yl)-propionic acid lactone, according to the procedure of Example 1.

Example 79 3-(17B-hydroxy 5 oxo 10cc desA-androstan-17ayl)-propionic acid lactone and 3-(17fi-hydroxy 5 oxodesA androstan 17a yl)-propionic acid lactone are prepared from 3-(17/3-hydroxy 5 oxo 3,5 seco- 39 A-nor-androstan 17oz yl 3 oic acid)-propionic acid lactone by conversion of the latter to its sodium salt followed by pyrolysis, according to the procedure of Example 2.

Example 80 3-(17/3-hydroxy 5 oxo desA androst 9 en- 17oc-yl)-propionic acid lactone is prepared from 3-(175- hydroxy 5 oxo 10a desA androstan 17oz yl)- propionic acid lactone by bromination followed by dehydrobromination, according to the procedure of Example 3.

Example 81 3-(17B hydroxy 5 oxo 9,8,10,43 desA-androstan- 17oz yl) propionic acid lactone is prepared from 3- (NB-hydroxy 5 oxo desA androst 9 en-l7a-yl)- propionic acid lactone by hydrogenation in the presence of a rhodium catalyst, according to the procedure of Example 4.

Example 82 3-(17/3 hydroxy 3 oxo 96,10 androst-4-en-17ayl)-propionic acid lactone is prepared by condensing 3- (175 hydroxy 5 oxo 95,101? desA androstan- 17a-yl)-propionic acid lactone with methyl vinyl ketone, according to the procedure of Example 5.

Example 83 17a,20;20,21 bis methylenedioxy 11oz mesyloxypregn 4 en 3 one is prepared by treatment of 17a, 20;20,2l-bis-methylenedioxy 11a hydroxy-pregn-4-en- 3-one with methanesulfonyl chloride according to the procedure of Example 10.

Example 84 17u,20;20,21 bis methylenedioxy 11a mesyloxy- 5-oxo 3,5 seco-A-norpregnan 3 oic acid is prepared by ozonolysis of 17nc,20;20,21 bis methylenedioxy-11amesyloxy-pregn 4 en 3 one according to the procedure of Example 11.

Example 85 17u,20;20,21 bis methylenedioxy desA pregn-9- en 5 one is prepared from 17a,20;20,21 bis-methylenedioxy 11a mesyloxy 5 oxo 3,5 seco-A-norpregnan 3 oic acid by conversion of the latter to its sodium salt followed by pyrolysis, according to the procedure of Example 12.

Example 86 17a,20;20,21 bis methylenedioxy 918,103 desA- pregnan 5 one is prepared from 17a,20;20,21-bis-methylenedioxy-desA-pregn 9 en 5 one by hydrogenation in the presence of a rhodium catalyst according to the procedure of Example 14.

Example 87 17oc,20;20,21 bis methylenedioxy 9,8,10a pregn- 4-en-3-one is prepared by condensing methylvinyl ketone with 17a,20;20,21 bis methylenedioxy 96,105 desA- pregnan-S-one, according to the procedure of Example 5.

Example 88 20,3 hydroxy 9 8,100; pregna 1,4 dien 3 one was prepared by condensation of 20B-hydroxy-9}9,10/8- desA-pregnan-S-one with 1 equivalent of methyl ethinyl ketone in boiling benzene solution, catalyzed by sodium hydride.

Example 89 One ml. of Jones reagent (0.004 mole CrO is added to 200 mg. of l7fi-hydroxy-9fl,l0fi-desA-androstan-5-one in 20 ml. of acetone at 10. The mixture is then left for minutes at room temperature, and 5 ml. of ethanol then added. The resulting suspension is evaporated to dryness in vacuo, water is added to the residue and the undissolved moiety taken up in ether. The ether phase is then washed with a solution of sodium bicarbonate and then with water, dried over sodium sulfate and evaporated to dryness. There is so obtained an oil which crystallizes upon the addition of a small portion of petroleum ether. The so-obtained crystals of 9,8,lOB-desA-androstane-S,17- dione melt, after recrystallization from cyclohexane, at 77.5-78";

(c.=0.107, dioxane); R.D. in dioxane (c.=0.10'7%): A in my. ([a]-value in 550 400 (+297); 350 (+798); 320 (+2968) max.; 300 (+467); 299 (0); 290 (+1890).

Example A solution of 250 mg. of 17p-hydroxy-9fl,l0, 3-desA- androstan 5 one dissolved in 2.5 ml. of pyridine and 2.5 ml. of acetic anhydride, is left at room temperature for 18 hours. The mixture is then evaporated to dryness at \80/11 mm., the residue taken up in ether, and the ether phase washed with l N hydrochloric acid, sodium bicarbonate and water, and then dried over sodium sulfate. After filtration and evaporation of the ether, the residue is then treated with a small quantity of petroleum ether yielding crystals of 17,8-acetoxy-9fi,IOfi-desA-androstan- 5-one which, upon recrystallization from methanol, melt at 118119;

(c.=0.103%, dioxane); R.D. in dioxane (c.-=0.103%): )t in ma ([a]-value in 400 (+30); 356 (0); 350 (+10); 313 (+449) max.; 307 (+374) min.; 305 (+380) max.; 300 (+224); 293 (0); 280 (652).

Example 91 A solution of 250 mg. of 17/3-acetoxy-95,10fl-desA- androstan-S-one in 60 ml. of 95% methanol containing 144 mg. of potassium hydroxide is refluxed for 60 minutes. The resulting mixture is evaporated to dryness in vacuo, water added to the residue and the suspension extracted with ether. The ether phase is washed with water, dried over sodium sulfate, filtered off, the solvent removed and the crystalline residue then crystallized from a small volume of cyclohexane, yielding crystals of 17B-hydroxy-9fl,IOfi-desA-androstan-S-one which upon being recrystallized from ethylacetate melt at 144.5-145;

(c.=0.103, dioxane), R.D. in dioxane (c.=0.103); A in my. ([ot]-value in 400 (-7); 390 (0); 350 (+52); 313 (+571) max; 307 (+492) min.; 305 (+504) max.; 300 (+324); 293 (0); 290 (+202).

Example 92 A solution of 10 g. of 1lfi-formyloxy-androsta-1,4- diene-3,l7-dione in ml. of acetic acid was ozonized at 0 until thin layer chromatography did not show any starting material. The reaction mixture was then poured into 100 ml. of water and the mixture was then heated to 100 for 30 minutes. The mixture was then concentrated in vacuo and treated with 50 ml. of saturated sodium bicarbonate solution. The undissolved material was ex tracted with 100 ml. of ether. The extract was chromatographed on silica gel using methylene chloride. The eluates were concentrated and gave, on addition of hexane, llB-formyloxy-l0g-desA-androstane 5,17 dione, M.P. 1171l7.5 (recrystallized from acetone-cyclohexane), [a] =93 (dioxane).

Example 93 By hydrolysis of llfl-formyloxy-lOE-desA-androstane- 5,17-dione in 2% methanolic potassium hydroxide there 

